Triazine based radiopharmaceuticals and radioimaging agents

ABSTRACT

Metal complexes including a radionuclide and a compound of Formula I and Formula II are potent inhibitors of PSMA.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is continuation of U.S. patent application Ser.No. 15/233,096, filed on Aug. 10, 2016, which is a divisional of U.S.patent application Ser. No. 14/152,864, filed on Jan. 10, 2014, now U.S.Pat. No. 9,447,121, and which claims the benefit of U.S. ProvisionalPatent Application Nos. 61/752,350, filed on Jan. 14, 2013, and61/785,788, filed on Mar. 14, 2013, all of which are incorporated hereinby reference in their entirety.

FIELD

The present technology relates generally to the field ofradiopharmaceuticals and their use in nuclear medicine as tracers,imaging agents and for the treatment of various disease states.

BACKGROUND

Many tumors express unique proteins that are predictors of malignancyand a poor prognosis. The expression of such proteins on the surface oftumor cells offers a unique opportunity to use such proteins as markersfor the diagnoses of a cancer condition, to evaluate the progression ofa cancer condition and to use such proteins as targets for the deliveryof a radiotherapeutic agent. Radioactive molecules that selectively bindto specific tumor cell surface proteins provide an attractive route forimaging and treating tumors under non-invasive conditions. Inparticular, the present invention provides radiolabeled ligands thatspecifically bind the prostate-specific membrane antigen (PSMA) protein,over expressed on many cancer cells, as agents for imaging or radiationbased therapy of PSMA-expressing cancer cells.

With over a million men suffering from prostate cancer, it is estimatedthat the disease will strike one in six U.S. men between the ages of 60and 80. There are more than 300,000 new cases of prostate cancerdiagnosed each year and the mortality from the disease is second only tolung cancer. An estimated $2 billion is currently spent worldwide onsurgical, radiation and drugs as treatments for prostate cancer. Thereis presently no effective therapy for relapsing, metastatic,androgen-independent prostate cancer. New agents that enable rapidvisualization of prostate cancer and specific targeting of this cancertissue for therapeutic purposes are presently needed.

Human prostate-specific membrane antigen (PSMA), also known as folatehydrolase I (FOLH1), is a trans-membrane, 750 amino acid type IIglycoprotein which is primarily expressed in the epithelium of normalhuman prostate tissue, but is upregulated in prostate cancer, includingmetastatic disease. PSMA is a unique exopeptidase with reactivity towardpoly-gamma-glutamated folates, capable of sequentially removing thepoly-gamma-glutamyl termini. Since PSMA is expressed by virtually allprostate cancers and its expression is further increased in poorlydifferentiated, metastatic and hormone-refractory carcinomas, it is avery attractive target for prostate imaging and therapy. Developingligands that interact with PSMA and carry appropriate radionuclides,therefore, may provide a promising and novel approach for the detection,treatment and management of prostate cancer.

The radio-immunoconjugate form of the anti-PSMA monoclonal antibody(mAb) 7E11, known as the PROSTASCINT scan, is currently being used todiagnose prostate cancer metastasis and recurrence. More recently,monoclonal antibodies that bind to the extracellular domain of PSMA andhave a radionuclide were shown to accumulate in PSMA-positive prostatetumor models in animals. However, diagnosis and tumor detection usingmonoclonal antibodies has been limited by the low permeability of themonoclonal antibody in solid tumor. Tumor detection using low molecularweight radiopharmaceutical compounds, therefore, hold promise and arebeing explored as potential diagnostic and radiotherapeutic alternativesto radioconjugates of monoclonal antibodies.

The selective targeting of cancer cells with radiopharmaceuticals,either for imaging or therapeutic purposes is challenging. A variety ofradionuclides are known to be useful for radio-imaging or cancerradiotherapy, including ¹¹¹In, ⁹⁰Y, ⁶⁸Ga, ¹⁷⁷Lu, ^(99m)Tc, ¹²³I and¹³¹I. Recently it has been shown that some compounds containing aglutamate-urea-glutamate (GUG) or a glutamate-urea-lysine (GUL)recognition element linked to a radionuclide-complex exhibit highaffinity for PSMA. Importantly, the present inventors found that theavidity of the GUL-radionuclide conjugate and GUG-radionuclide conjugatedepends at least in part on the chemical nature and size of the linkeror spacer joining the GUL or GUG group to the radionuclide complex.

The present invention focuses on GUL-radiocomplexes orGUG-radiocomplexes that have a one or more optionally substitutedtriazene groups as part of a linker conjugating the GUL or GUG groups tothe radiocomplex. More specifically, the present invention explores thestructure-function activity of such triazine-based linkers, for instanceby exploring the relationship between binding affinity and linker lengthas well as the relationship between binding affinity and the position ofthe optionally substituted triazine moiety such as apiperazinyl-triazine-p-aminobenzyl group within the linker. Alsodescribed are methods for synthesizing the triazine basedradiopharmaceuticals, as well as methods for characterization and forusing the inventive GUL-radionuclide and GUG-radionuclide conjugates forthe diagnosis and treatment of cancer.

SUMMARY

The present invention relates to compounds having a PSMA targetingmoiety linked to a radionuclide chelating group as well as radionuclidecomplexes of the inventive compounds. More specifically, the presenttechnology is focued on the synthesis and use of compounds that conformto the general structure [PSMA recognition motif]-linker-[radionuclidechelating group] and radionuclide complexes of the inventive compounds.As further described below, the inventive compounds and theirradionuclide complexes comprise a 1,3,5-triazine moiety within thelinker. The incorporation of the 1,3,5-triazine group has advantagessince it provides three sites of attachments for the PSMA recognitionmotif and radionuclide chelating group and also improves thepharmacokinetic properties of the inventive compounds and theirradionuclide complexes.

The invention also provides pharmaceutically acceptable formulations ofthe inventive compounds and their radionuclide complexes. Suchformulations are suitable for treating a variety of disease conditionsincluding without limitation prostate cancer, breast cancer, colorectalcancer, brain cancer, lung cancer, liver cancer, endometrial cancer,bone cancer, ovarian cancer, testicular cancer, skin cancer, pancreaticcancer, uterine cancer, cervical cancer, bladder cancer, esophagealcancer, gastric cancer, head and neck cancers, or kidney cancer.

In one embodiment therefore, are provided compounds that conform toFormula I and to stereoisomers, tautomers, prodrugs, andpharmaceutically acceptable salts or esters thereof.

In Formula I, A is (CHR¹)_(m) or C(O) and W is selected from the groupconsisting of —C(O)—(CH₂)_(p)—; —C(O)[—CH₂—CH₂—O]_(n)—,—[CH₂—CH₂—O]_(n)—(CH₂)₂—, —C(O)—[CH(R³)_(t)]_(q)—,—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,—(CH₂)_(m)—S(O)—(CH₂)_(n)—, —(CH₂)_(m)—S(O)₂—(CH₂)_(n)—, and—(CH₂)_(m)—NR_(a)—(CH₂)_(n)—. Substituent Y is selected from —NH—,—NR²—, or

while X in Formula I is selected from —(C₁-C₁₀)alkylene-(C₃-C₁₀)arylene,—(C₃-C₁₀)arylene, —(C₃-C₁₀)arylene-(C₁-C₁₀)alkylene-, phenylene,—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkylene, —(C₃-C₁₀)cycloalkylene, or—(C₃-C₁₀)cycloalkylene-(C₁-C₁₀)alkylene-.

R¹ and R² in Formula I can each independently selected from H,—(C₁-C₁₀)alkyl, —C(O)—(C₁-C₁₀)alkyl, benzyl, —(C₃-C₁₀)cycloalkyl, or—(C₃-C₁₀)aryl. For Formula I compounds, R^(a) and R^(b) are eachindependently selected from the group consisting of H, —OH,—(C₁-C₁₀)alkyl, —[CH₂—CH₂—O]_(n)—(CH₂)₂-T, —C(O)—(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—Z, benzyl,—(C₃-C₁₀)cycloalkyl, —(C₃-C₁₀)aryl-(C₁-C₁₀)alkylene, —(C₃-C₁₀)aryl,halo-(C₁-C₁₀)alkyl, hydroxy-(C₁-C₁₀)alkyl, —NH—(C₁-C₁₀)alkyl, and—(C₁-C₁₀)alkylene-NR^(d)R^(e)—, or R^(a) and R^(b) together with thenitrogen to which they are bonded form a (C₃-C₆)-heteroaryl or(C₃-C₆)-heterocycloalkyl that can further comprise one or moreheteroatoms selected from N, S, or O.

Z in Formula I is selected from —OH, —O(C₁-C₁₀)alkyl,

and substituent R^(c) can be selected from —OH, —O(C₁-C₁₀)alkyl,-Obenzyl, —O(C₃-C₁₀)cycloalkyl, —O(C₃-C₁₀)aryl,—O—(C₁-C₁₀)alkylene-(C₃-C₁₀)aryl, or—O—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkyl.

For Formula I compounds, R³ is selected from H, halogen, —OH, —NH₂,—(CH₂)_(p)—COOH, or —(CH₂)_(p)— NH₂, substituent T is selected from —H,—OH, —COOH, or —NR^(d)R^(e) and R^(d) and R^(e) are each independentlyselected from H, bond, —OH, —(C₁-C₁₀)alkyl, or—(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene. Subscripts m, n, p, q, t and r inFormula I are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10; andgroup D is selected from

Any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene,cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene inFormula I is optionally substituted with 1, 2, or 3 substituent groupsselected from the group consisting of —(C₁-C₁₀)alkyl,—(C₁-C₁₀)haloalkyl, —(C₁-C₁₀) aminoalkyl, —(C₁-C₁₀)alkylene-COOH,—(C₁-C₁₀)hydroxyalkyl, —OH, halogen, —NH₂, —COOH, —C(O)—(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—X, —NH—(C₁-C₁₀)alkyl,and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, and —NR^(d)R^(e). Pursuant to thesedefinitions, for certain Formula I compounds, X is phenylene, r is 1 andD is

The present invention also provides compounds that conform to FormulaII, to stereoisomers, tautomers, prodrugs, and pharmaceuticallyacceptable salts or esters thereof, and to their pharmaceuticallyacceptable formulations as therapeutics for treating various diseasesstates associated uncontrolled proliferation of cells.

In Formula II, A is (CHR¹)_(m) or C(O) and substituent W is selectedfrom the group consisting of —C(O)—(CH₂)_(p)—; —C(O)[—CH₂—CH₂—O]_(n)—,—[CH₂—CH₂—O]_(n)—(CH₂)₂—, —C(O)—[CH(R³)_(t)]_(q)—,—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,—(CH₂)_(m)—S(O)—(CH₂)_(n)—, —(CH₂)_(m)—S(O)₂—(CH₂)_(n)—, and—(CH₂)_(m)—NR_(a)—(CH₂)_(n)—.

Group Y in Formula II is selected from —NH—, —NR²—,

while variables R¹ and R² are each independently selected from H,—(C₁-C₁₀)alkyl, —C(O)—(C₁-C₁₀)alkyl, benzyl, —(C₃-C₁₀)cycloalkyl, or—(C₃-C₁₀)aryl.

In Formula II, R^(a) and R^(b) are each independently selected from thegroup consisting of H, —OH, —(C₁-C₁₀)alkyl, —[CH₂—CH₂—O]_(n)—(CH₂)₂-T,—C(O)—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—Z,benzyl, —(C₃-C₁₀)cycloalkyl, —(C₃-C₁₀)aryl-(C₁-C₁₀)alkylene,—(C₃-C₁₀)aryl, halo-(C₁-C₁₀)alkyl, hydroxy-(C₁-C₁₀)alkyl,—NH—(C₁-C₁₀)alkyl, and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—. Alternatively,R^(a) and R^(b) together with the nitrogen to which they are bonded forma (C₃-C₆)-heteroaryl or (C₃-C₆)-heterocycloalkyl that can furthercomprise one or more heteroatoms selected from N, S, or O.

Z in Formula II is selected from —OH, —O(C₁-C₁₀)alkyl,

and substituent R^(c) is selected from —OH, —O(C₁-C₁₀)alkyl, -Obenzyl,—O(C₃-C₁₀)cycloalkyl, —O(C₃-C₁₀)aryl, —O—(C₁-C₁₀)alkylene-(C₃-C₁₀)aryl,or —O—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkyl.

For Formula II compounds R³ is selected from H, halogen, —OH, —NH₂,—(CH₂)_(p)—COOH, or —(CH₂)_(p)—NH₂, T is selected from —H, —OH, —COOH,or —NR^(d)R^(e) and each of R^(d) and R^(e) are independently selectedfrom H, bond, —OH, —(C₁-C₁₀)alkyl, or—(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene.

Any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene,cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene inFormula II can be optionally substituted with 1, 2, or 3 substituentgroups selected from the group consisting of —(C₁-C₁₀)alkyl,—(C₁-C₁₀)haloalkyl, —(C₁-C₁₀) aminoalkyl, —(C₁-C₁₀)alkylene-COOH,—(C₁-C₁₀)hydroxyalkyl, —NH₂, —COOH, —C(O)—(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—X, —NH—(C₁-C₁₀)alkyl,and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, and —NR^(d)R^(e) and subscripts m,n, p, q, t and x are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or10;

For certain Formula II compounds A is (CH₂)_(m), W is —C(O)—(CH₂)_(p)—and Y is —NH— or

In one embodiment, A is (CH₂)₂, W is —C(O)—(CH₂)₇— or —C(O)—(CH₂)₁₀— andY is

with R^(a) and R^(b) each independently being hydrogen or methyl andsubstituent R^(c) is —OH.

In one embodiment, R^(a) and R^(b) together with the nitrogen to whichthey are bonded form a (C₃-C₆)-heterocycloalkyl, for example, a groupselected from piperidine, piperazine, morpholine, thiomorpholine,isothiazolidine, isoxazolidine, pyrrolidine, immidazolidine,thiazolidine, oxazolidine, or 4-(piperidin-4-yl)butanoic acid.

For certain other Formula II compounds, R^(a) is —H and R^(b) is

with groups R^(d) and R^(e) each independently being a—(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene, such as

Also encompassed by the present technology are metal complexescomprising a radionuclide and a compound according to Formula I orFormula II. The radionuclide used is selected from the group consistingof ¹¹¹In, ⁹⁰Y, ⁶⁸Ga, ⁶⁴Cu, ¹⁵³Gd, ¹⁵⁵Gd, ¹⁵⁷Gd, ⁵⁹Fe, ²²⁵Ac, ²¹²Bi,²¹³Bi, ⁵⁵Co, ⁶⁷Cu, ¹⁶⁵Dy, ¹⁶⁶Ho, ¹⁹²Ir, ²²³Ra, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁰⁵Rh,²¹²Pb, ²¹³Pb, ¹⁴⁹Tb, 227Th, ¹⁵³Sm, 89Sr, ^(117m)Sn, ¹⁶⁹Yb, ⁹⁰Y, 86Y,⁸⁹Zr and ¹⁷⁷Lu.

The present invention also provides a pharmaceutically acceptable salt,stereoisomer, tautomer, or prodrug of a Formula I or a Formula IIcompound as well as the radionuclide complexes of Formula I or FormulaII compounds.

Radionuclide complexes of Formula I or II compounds and theirpharmaceutical formulations are useful for obtaining radiographic imagesor for treating a number of diseases and conditions, including but notlimited to prostate cancer, breast cancer, colon cancer, brain cancer,lung cancer, liver cancer, endometrial cancer, bone cancer, ovariancancer, or kidney cancer.

In one embodiment, the invention provides a method of obtaining aradiographic image of one or more tissues that express prostate-specificmembrane antigen (PSMA) by (a) contacting one or more tissues thatexpress PSMA with a metal complex comprising a radionuclide and acompound according to Formula III

or a pharmaceutically acceptable salt or solvate thereof; and (b)recording a radiographic image of the one or more tissues.

Pursuant to this methodology, variable G in Formula III is

L is selected from —NH—(C₁-C₁₀)alkylene-, —NH—(C₁-C₁₀)alkylene-C(O)—,—C(O)—(C₁-C₁₀)alkylene-, —C(O)—(C₁-C₁₀)alkylene-C(O)— or

and R^(a) and R^(b) are each independently selected from the groupconsisting of H, —OH, —(C₁-C₁₀)alkyl, —[CH₂—CH₂—O]_(n)—(CH₂)₂-T,—C(O)—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—Z,benzyl, —(C₃-C₁₀)cycloalkyl, —(C₃-C₁₀)aryl-(C₁-C₁₀)alkylene,—(C₃-C₁₀)aryl, halo-(C₁-C₁₀)alkyl, hydroxy-(C₁-C₁₀)alkyl,—NH—(C₁-C₁₀)alkyl, and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—.

For certain Formula III compounds R^(a) and R^(b) together with thenitrogen to which they are bonded form a (C₃-C₆)-heteroaryl or(C₃-C₆)-heterocycloalkyl that can further comprise one or moreheteroatoms selected from N, S, or O.

Substituent Z in Formula III is selected from —OH, —O(C₁-C₁₀)alkyl,

substituents R^(d) and R^(e) are each independently selected from H,bond, —OH, —(C₁-C₁₀)alkyl, or —(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene andsubscript n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or10.

Pursuant to one embodiment, as noted above, the invention provides aradionuclide complex of Formula I or Formula II compounds astherapeutics for treating a subject diagnosed with cancer for instanceprostate cancer. Treatment according to the inventive methodology iseffected by administering to a subject a therapeutically effectiveamount of a prostate-specific membrane antigen (PSMA) binding complexcomprising a triazinylene linker and capable of being retained in aPSMA-expressing tumor tissue for a longer interval of time than non-PSMAexpressing tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates tissue biodistribution of the ¹⁷⁷Lu-complex of(2S)-2-(3-(1-carboxy-5-(11-(4-(4-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid according to the present invention in LNCap Xenograft mice.

FIG. 2 illustrates tissue biodistribution of the ¹⁷⁷Lu-complex of(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid according to the present invention in LNCap Xenograft mice.

FIG. 3 illustrates tissue biodistribution of the ¹⁷⁷Lu-complex of (21S,25S)-8,15,23-trioxo-1-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1thioxo-2,7,16,22,24-pentaazaheptacosane-21,25,27-tricarboxylicacid used as a control in LNCap Xenograft mice.

FIG. 4 illustrates tissue biodistribution of the ¹⁷⁷Lu-complex of(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid according to the present invention in LNCap Xenograft mice.

FIG. 5 illustrates in vivo inhibition of LNCaP tumor growth by¹⁷⁷Lu-complex of(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid.

FIG. 6 illustrates a radiographic image obtained by administering to asubject having prostate cancer a ⁶⁸Ga complex of(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioic acid.

DETAILED DESCRIPTION

There are two categories of radiopharmaceuticals: (i) those withbiological distribution determined strictly by blood flow, or perfusion,and targeting high capacity systems such as glomerular filtration,phagocytosis, hepatocyte clearance and bone absorption and (ii) thosewith distribution determined by specific enzymatic or receptor bindinginteractions, which are low-capacity sites. The radiopharmaceuticalsaccording to Formula I or Formula II belong to the second category andare synthesized by conjugating the radionuclide coordination complex toa biologically active molecule selective for PSMA protein using a linkerthat has a traizine moiety.

The terms “linker,” “spacer,” “linker group” or “spacer group” are usedinterchangeably in this document and refer to a group that spans thedistance between two other identified groups, or which “spaces” themapart. The linker or spacer may be a bond, an organic group, or aninorganic group or atom.

In some embodiments, the linker or spacer is an optionally substituted(C₁-C₁₅)alkylene, a (C₂-C₁₅)alkenylene, a (C₂-C₁₅)alkynylene group,a-C(O)—(C₁-Cis)alkylene-, a —C(O)—(C₃-C₁₅)arylene-(C₁-C₁₅)alkylene-,—W—Y—(C₃-C₁₅)heteroarylene-NH—X—(CH₂)_(r)—, or a—C(O)—(C₁-C₁₅)alkylene-Y—(C₃-C₁₅)heteroarylene-NH—X—, where thevariables “W”, “X” and “Y” are further described below. Illustrativesubstituent groups include without limitation carboxyl groups,carboxylate, hydroxyl groups, and amino (NR^(a)R^(b)) groups. Forcertain embodiments, the (C₁-C₁₅)alkylene group in the linker describedabove can be replaced by a (C₁-C₁₅)polyol, for example, a polyethyleneglycol (PEG) moiety. Exemplary linker or spacer groups are illustratedwithout limitation throughout the specification and working examples.

For convenience, certain terms employed herein and within the appendedclaims are defined here.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particular term.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the elements (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext.

The terms “lipophilic group” and “lipophilic moiety” as used hereinrefer to a group, moiety or substituent that has a greater affinity fornon-polar or non-aqueous environments versus polar or aqueousenvironments. For example, Merriam Webster's online dictionary defines“lipophilic” as “having an affinity for lipids (as fats).” Illustrativelipophilic moieties include aliphatic hydrocarbon radicals, e.g., alkylradicals, aromatic hydrocarbon radicals, and long-chain acyl radicals;all of them have increasing lipophilicity as the number of constituentcarbons increases. In general, addition of a lipophilic moiety to aparticular compound will increase the compound's affinity for octanol inthe standard octanol/water partition-coefficient-determination protocol;this protocol may be used to gauge a compound's relative hydrophobicity(lipophilicity) and hydrophilicity.

The term “ligand” refers to a species that interacts in some fashionwith another species. In one example, a ligand may be a Lewis base thatis capable of forming a coordinate bond with a Lewis Acid. In otherexamples, a ligand is a species, often organic, that forms acoordination complex with a metal ion. In biochemistry and pharmacology,a ligand is a substance (usually a small molecule), that forms a complexwith a biomolecule to serve a biological purpose. In a narrower sense, aligand is a signal triggering molecule, binding to a site on a targetprotein. The binding occurs by intermolecular forces, such as ionicbonds, hydrogen bonds and van der Waals forces.

The term “chelating agent” refers to a molecule, often an organic one,and often a Lewis base, having two or more unshared electron pairsavailable for donation to a metal ion. The metal ion is usuallycoordinated by two or more electron pairs to the chelating agent. Theterms, “bidentate chelating agent”, “tridentate chelating agent”, and“tetradentate chelating agent” are art-recognized and refer to chelatingagents having, respectively, two, three, and four electron pairs readilyavailable for simultaneous donation to a metal ion coordinated by thechelating agent. Usually, the electron pairs of a chelating agent formscoordinate bonds with a single metal ion; however, in certain examples,a chelating agent may form coordinate bonds with more than one metalion, with a variety of binding modes being possible.

The term “coordination” refers to an interaction in which onemulti-electron pair donor coordinatively bonds (is “coordinated”) to onemetal ion.

The term radionuclide refers to an atom with an unstable nucleus, whichis a nucleus characterized by excess energy available to be impartedeither to a newly created radiation particle within the nucleus or to anatomic electron. The radionuclide can undergo radioactive decay and inthe process emit subatomic ionizing particles. Illustrative of subatomicionizing particles without limitation are alpha (α) particles, beta (β)particle and gamma (γ) rays. Exemplary radionuclides include withoutlimitation elements belonging to the lanthanide series, actinide seriesas well as radioisotpes of transition metals. Illustrative radionuclidesmay include, but are not limited to ¹¹¹In, ⁹⁰Y, ⁶⁸Ga, ⁶⁴Cu, ¹⁵³Gd,¹⁵⁵Gd, ¹⁵⁷Gd, 59Fe, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁵⁵Co, ⁶⁷Cu, ¹⁶⁵Dy, ¹⁶⁶Ho,¹⁹²Ir, ²²³Ra, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁰⁵Rh ²¹²Pb, ²¹³Pb, ¹⁴⁹Tb, ²²⁷Th, ¹⁵³Sm,⁸⁹Sr, ^(117m)Sn, ¹⁶⁹Yb, ⁹⁰Y, ⁸⁶Y, ⁸⁹Zr and ¹⁷⁷Lu. However, the term isnot limited to these four radionuclides.

Fmoc is an abbreviation for the chemical group:fluorenylmethyloxycarbonyl.

The phrases “effective amount” or “therapeutically-effective amount” asused herein means that amount of a compound, material, or compositioncomprising a compound of the invention, or other active ingredient whichis effective for producing some desired therapeutic effect in at least asub-population of cells in an animal at a reasonable benefit/risk ratioapplicable to any medical treatment. A therapeutically effective amountwith respect to a compound of the invention means that amount oftherapeutic agent alone, or in combination with other therapies, thatprovides a therapeutic benefit in the treatment or prevention of adisease. Used in connection with a compound of the invention, the termcan encompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of disease, or enhances the therapeutic efficacy ofor synergies with another therapeutic agent.

As used herein, the terms “treating” or “treatment” is intended toencompass also diagnosis, prophylaxis, therapy and cure. The patientreceiving this treatment is any animal in need, including primates, inparticular humans, and other mammals such as equines, cattle, swine andsheep; and poultry and pets in general.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, or solvent encapsulatingmaterial, involved in carrying or transporting the subject compound fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycarbonates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

A “pharmaceutically acceptable salt” is a pharmaceutically acceptable,organic or inorganic acid or base salt of a compound of the invention.Representative pharmaceutically acceptable salts include, e.g., alkalimetal salts, alkali earth salts, ammonium salts, water-soluble andwater-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2, 2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrastemal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

A “patient” includes an animal, such as a human, cow, horse, sheep,lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit orguinea pig. The animal can be a mammal such as a non-primate and aprimate (e.g., monkey and human). In one embodiment, a patient is ahuman, such as a human infant, child, adolescent or adult.

The term “prodrug” refers to a precursor of a drug that is a compoundwhich upon administration to a patient, must undergo chemical conversionby metabolic processes before becoming an active pharmacological agent.Illustrative prodrugs of compounds in accordance with Formula I areesters, preferably alkyl esters or fatty acid esters.

The term “heteroatom” refers to an atom of any element other than carbonor hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen,phosphorus, sulfur and selenium.

In general, “substituted” refers to an alkyl, alkylene, alkenyl,alkenylene, alkyne, alkynylene, aryl, arylene, cycloalkyl, orcycloalkylene group, as defined below in which one or more bonds to ahydrogen atom contained therein are replaced by a bond to non-hydrogenor non-carbon atoms. Substituted groups also include groups in which oneor more bonds to a carbon(s) or hydrogen(s) atom are replaced by one ormore bonds, including double or triple bonds, to a heteroatom. Thus, asubstituted group will be substituted with one or more substituents,unless otherwise specified. In some embodiments, a substituted group issubstituted with 1, 2, 3, 4, 5, or 6 substituents. Examples ofsubstituent groups include: halogens (i.e., F, Cl, Br, and I);hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy,heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo);carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines;aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls;sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones;azides; amides; ureas; amidines; guanidines; enamines; imides;isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitrogroups; nitriles (i.e., CN), haloalkyl, aminoalkyl, hydroxyalkyl,cycloalkyl and the like.

Alkyl groups include straight chain and branched chain alkyl groupshaving from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or,in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms.Examples of straight chain alkyl groups include groups such as methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octylgroups. Examples of branched alkyl groups include, but are not limitedto, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl,and 2,2-dimethylpropyl groups. Alkyl groups may be substituted orunsubstituted. Unless the number of carbons is otherwise specified,“lower alkyl” refers to an alkyl group, as defined above, but havingfrom one to about ten carbons, alternatively from one to about sixcarbon atoms in its backbone structure. Likewise, “lower alkenyl” and“lower alkynyl” have similar chain lengths.

The terms “alkylene” and “substituted alkylene” refer to divalent alkyland divalent substituted alkyl, respectively. Examples of alkyleneinclude without limitation, ethylene (—CH₂—CH₂—). “Optionallysubstituted alkylene” refers to alkylene or substituted alkylene.

The term “alkylcarbonyl” or “alkylenecarbonyl” denote a—(C₁-C₈)alkyl-C(O)— or —C(O)—(C₁-C₈)alkyl- groups in which at least oneof the methylenes in the C₁-C₈ alkyl group is replaced with a C(O)group. Representative examples include, but are not limited to, acetyl,propionyl, and CH₃(CH₂)₂C(O)— group, or —CH₂(CH₂)₂C(O)—.

The terms “cyclic alkyl” or “cycloalkyl” refers to a saturated orpartially saturated non-aromatic cyclic alkyl groups of from 3 to 14carbon atoms and no ring heteroatoms and having a single ring ormultiple rings including fused and bridged ring systems. Cycloalkylgroups may be substituted or unsubstituted. Cycloalkyl or cyclic alkylgroups include mono-, bi- or tricyclic alkyl groups having from 3 to 14carbon atoms in the ring(s), or, in some embodiments, 3 to 12, 3 to 10,3 to 8, or 3 to 4, 5, 6 or 7 carbon atoms. Illustrative monocycliccycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Bi- andtricyclic ring systems include both bridged cycloalkyl groups and fusedrings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl,decalinyl, and the like.

A “cycloalkylene” is a divalent saturated or partially saturatednon-aromatic cyclo alkyl groups having 3 to 14 carbon atoms and no ringheteroatoms.

Alkenyl groups include straight and branched chain and cycloalkyl groupsas defined above, except that at least one double bond exists betweentwo carbon atoms. Thus, alkenyl groups have from 2 to about 12 carbonatoms in some embodiments, from 2 to 10 carbon atoms in otherembodiments, and from 2 to 8 carbon atoms in other embodiments. Examplesinclude, but are not limited to vinyl, allyl, —CH═CH(CH₃), —CH═C(CH₃)₂,—C(CH₃)═CH₂, —C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, cyclohexenyl,cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl,among others. Alkenyl groups may be substituted or unsubstituted.Representative substituted alkenyl groups may be mono-substituted orsubstituted more than once, such as, but not limited to, mono-, di- ortri-substituted with substituents such as those listed above.

The term “alkenylene” refers to divalent alkene. Examples of alkenyleneinclude without limitation, ethenylene (—CH═CH—) and all stereoisomericand conformational isomeric forms thereof. “Substituted alkenylene”refers to divalent substituted alkene. “Optionally substitutedalkenylene” refers to alkenylene or substituted alkenylene.

“Alkyne” or “alkynyl” refers to straight and branched chain unsaturatedhydrocarbon having the indicated number of carbon atoms and at least onetriple bond. Examples of a (C₂-C₈)alkynyl group include, but are notlimited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne,2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne,3-heptyne, 1-octyne, 2-octyne, 3-octyne and 4-octyne. An alkynyl groupcan be unsubstituted or optionally substituted with one or moresubstituents as described herein below.

The term “alkynylene” refers to divalent alkyne. Examples of alkynyleneinclude without limitation, ethynylene, propynylene. “Substitutedalkynylene” refers to divalent substituted alkyne.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Aryl groups include monocyclic, bicyclic and polycyclicring systems. Thus, aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl,indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments,aryl groups contain 6-14 carbons, and in others from 3 to 12 or even3-10 carbon atoms in the ring portions of the groups. Aryl groupincludes both substituted and unsubstituted aryl groups. Substitutedaryl groups may be mono-substituted or substituted more than once. Forexample, monosubstituted aryl groups include, but are not limited to,2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may besubstituted with substituent groups such as those listed above.

“Arylene” denotes divalent aryl, and “substituted arylene” refers todivalent substituted aryl. “Optionally substituted arylene” refers toarylene or substituted arylene. Illustrative of the arylene group isphenylene.

“Heterocycloalkyl” means a saturated or unsaturated non-aromaticmonocyclic, bicyclic, tricyclic or polycyclic ring system that has from5 to 14 atoms in which from 1 to 3 carbon atoms in the ring are replacedby heteroatoms of O, S or N. A heterocycloalkyl is optionally fused withbenzo or heteroaryl of 5-6 ring members, and includes oxidized S or N,such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. Thepoint of attachment of the heterocycloalkyl ring is at a carbon orheteroatom such that a stable ring is retained. Examples ofheterocycloalkyl groups include without limitation morpholino,tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl,piperazinyl, dihydrobenzofuryl, and dihydroindolyl.

“Optionally substituted heterocycloalkyl” denotes heterocycloalkyl thatis substituted with 1 to 3 substituents, e.g., 1, 2 or 3 substituents,attached at any available atom to produce a stable compound, wherein thesubstituents are as described herein.

The term “cycloalkyl” refer to monocyclic, bicyclic, tricyclic, orpolycyclic, 3- to 14-membered ring systems, which are either saturated,unsaturated or aromatic. The cycloalkyl group may be attached via anyatom. Cycloalkyl also contemplates fused rings wherein the cycloalkyl isfused to an aryl or hetroaryl ring as defined above. Representativeexamples of cycloalkyl include, but are not limited to cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group can beunsubstituted or optionally substituted with one or more substituents asdescribed herein below.

The term “cycloalkylene” refers to divalent cycloalkyl. The term“optionally substituted cycloalkylene” refers to cycloalkylene that issubstituted with 1 to 3 substituents, e.g., 1, 2 or 3 substituents,attached at any available atom to produce a stable compound, wherein thesubstituents are as described herein.

The term “(C₃-C₁₄)aryl-(C₁-C₆)alkylene” refers to a divalent alkylenewherein one or more hydrogen atoms in the C₁-C₆ alkylene group isreplaced by a (C₃-C₁₄)aryl group. Examples of(C₃-C₁₄)aryl-(C₁-C₆)alkylene groups include without limitation1-phenylbutylene, phenyl-2-butylene, 1-phenyl-2-methylpropylene,phenylmethylene, phenylpropylene, and naphthylethylene.

The term “(C₁-C₁₀)alkylene-(C₃-C₁₄)arylene” refers to a divalent arylenein which one or more hydrogen atoms in the C₃-C₁₄ arylene is replaced bya (C₁-C₁₀)alkyl group and wherein one of the hydrogens of the alkylgroup is replaced by another group. Examples of“(C₁-C₁₀)alkylene-(C₃-C₁₄)arylene groups include without limitationbutylene-4-phenylene, propylene-2-phenylene, and 1-[2-methylpropylene]phenylene.

The term “(C₃-C₁₄)arylene-(C₁-C₁₀)alkylene” refers to a divalentalkylene in which one or more hydrogen atoms in the C₁-C₁₀ alkylene isreplaced by a divalent (C₃-C₁₄)arylene group. Exemplary of“(C₃-C₁₄)arylene-(C₁-C₁₀)alkylene group include without limitationphenylene-4-butylene, phenylene-2-butylene, andphenylene-1-[2-methylpropylene].

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. In some embodiments, aralkyl groups contain 7 to 20carbon atoms, 7 to 14 carbon atoms or 7 to 10 carbon atoms.

“Heterocyclyl” or heterocycloalkyl refers to non-aromatic ring compoundscontaining 3 or more ring members, of which one or more ring carbonatoms are replaced with a heteroatom such as, but not limited to, N, O,and S. In some embodiments, heterocyclyl groups include 3 to 20 ringmembers, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3to 15 ring members. Heterocyclyl groups encompass unsaturated, partiallysaturated and saturated ring systems, such as, for example, imidazolyl,imidazolinyl and imidazolidinyl groups. Heterocyclyl groups may besubstituted or unsubstituted. Heterocyclyl groups include, but are notlimited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl,dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl,imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl,pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl,quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl(pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl,benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl,benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl),triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl,thianaphthalenyl, dihydrobenzothiazinyl, dihydrobenzofuranyl,dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl,tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl,tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl,tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, andtetrahydroquinolinyl groups. Heterocyclyl groups may be substituted orunsubstituted. Representative substituted heterocyclyl groups may bemono-substituted or substituted more than once, such as, but not limitedto, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or6-substituted, or disubstituted with various substituents such as thoselisted above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more ring carbon atoms are replaced withheteroatom such as, but not limited to, N, O, and S. Heteroaryl groupsmay be substituted or unsubstituted. Heteroaryl groups include, but arenot limited to, groups such as pyrrolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl,benzofuranyl, indolyl, azaindolyl (pyrrolopyridyl), indazolyl,benzimidazolyl, imidazopyridyl (azabenzimidazolyl), pyrazolopyridyl,triazolopyridyl, benzotriazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl,purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

The term “alkoxy” refers to an —O-alkyl group having the indicatednumber of carbon atoms. For example, a (C₁-C₁₀)alkoxy group includes—O-methyl (methoxy), —O-ethyl (ethoxy), —O-propyl (propoxy),—O-isopropyl (isopropoxy), —O-butyl (butoxy), —O-sec-butyl (sec-butoxy),—O-tert-butyl (tert-butoxy), —O-pentyl (pentoxy), —O-isopentyl(isopentoxy), —O— neopentyl (neopentoxy), —O-hexyl (hexyloxy),—O-isohexyl (isohexyloxy), and —O-neohexyl (neohexyloxy). Examples ofcycloalkoxy groups include but are not limited to cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxygroups may be substituted or unsubstituted.

The term “carbocycle” refers to an aromatic or non-aromatic ring inwhich each atom of the ring is carbon.

The term “nitro” refers to —NO₂.

The term “halogen” is art-recognized and refers to —F, —Cl, —Br or —I;the term “sulfhydryl” is art-recognized and refers to —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” is art-recognized andrefers to —SO₂—. “Halide” designates the corresponding anion of thehalogens, and “pseudohalide” has the definition set forth on 560 of“Advanced Inorganic Chemistry” by Cotton and Wilkinson.

The term “amine or amino” refers to an —NR^(d)R^(e) group wherein R^(d)and R^(e) each independently refer to a hydrogen, (C₁-C₈)alkyl, aryl,heteroaryl, and heterocycloalkyl group. When R^(d) and R^(e) areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. For example,—NR^(d)R^(e) is meant to include 1-pyrrolidinyl, pyridinyl or a4-morpholinyl ring.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that may be represented by the general formula,—C(O)NR^(d)R^(e) group wherein R^(d) and R^(e) are as defined above.

The term “nitrile or cyano” can be used interchangeably and refer to a—CN group which is bound to a carbon atom of a heteroaryl ring, arylring and a heterocycloalkyl ring.

The term “aminoalkyl,” refers to an (C₁-C₁₀)alkyl group wherein one ormore hydrogen atoms in the (C₁-C₁₀)alkyl group is replaced with a—NR^(d)R^(e) group, where R^(d) and R^(e) can be the same or different,for example, R^(d) and R^(e) each independently refer to a hydrogen,(C₁-C₈)alkyl, aryl, heteroaryl, heterocycloalkyl, (C₁-C₈)haloalkyl, and(C₁-C₁₀)hydroxyalkyl group. Examples of aminoalkyl groups include, butare not limited to, aminomethyl, aminoethyl, 4-aminobutyl and3-aminobutylyl.

The term “haloalkoxy,” refers to an —O—(C₁-C₈)alkyl group wherein one ormore hydrogen atoms in the C₁-C₈ alkyl group is replaced with a halogenatom, which can be the same or different. Examples of haloalkyl groupsinclude, but are not limited to, difluoromethocy, trifluoromethoxy,2,2,2-trifluoroethoxy, 4-chlorobutoxy, 3-bromopropyloxy,pentachloroethoxy, and 1,1,1-trifluoro-2-bromo-2-chloroethoxy.

The term “hydroxyalkyl,” refers to an alkyl group having the indicatednumber of carbon atoms wherein one or more of the alkyl group's hydrogenatoms is replaced with an —OH group. Examples of hydroxyalkyl groupsinclude, but are not limited to, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂CH₂OH, and branchedversions thereof.

A “hydroxyl” or “hydroxy” refers to an —OH group.

The terms “carboxyl” and “carboxylate” include such moieties as may berepresented by the general formulas:

wherein E is a bond or represents O or S, and R^(f) and R^(f′)individually is H, alkyl, alkenyl, aryl, or a pharmaceuticallyacceptable salt. Where E is O, and R^(f) is as defined above, the moietyis referred to herein as a carboxyl group, and particularly when R^(f)is a hydrogen, the formula represents a “carboxylic acid”. In general,where the expressly shown oxygen is replaced by sulfur, the formularepresents a “thiocarbonyl” group.

The substituent —CO₂H, may be replaced with bioisosteric replacementssuch as:

and the like, wherein R has the same definition as R′ and R″ as definedherein. See, e.g., THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press:New York, 1996), at page 203.

The terms “alkoxyl” or “alkoxy” refer to an alkyl group, as definedabove, having an oxygen radical attached thereto. Representative alkoxylgroups include methoxy, ethoxy, propoxy, butyoxy, tert-butoxy and thelike. An “ether” is two hydrocarbons covalently linked by an oxygen.“Ether” also encompasses polyethers where more than one ether group, orlinkage, may be present in a given group. “Ether” also encompassescyclic ethers, and crown ethers, where the ether linkage is within acyclic group.

The term “(C₅-C₁₄)aryl-(C₁-C₁₀)alkylene” refers to a divalent alkylenewherein one or more hydrogen atoms in the C₁-C₁₀ alkylene group isreplaced by a (C₃-C₁₄)aryl group. Examples of(C₃-C₁₄)aryl-(C₁-C₁₀)alkylene groups include without limitation1-phenylbutylene, phenyl-2-butylene, 1-phenyl-2-methylpropylene,phenylmethylene, phenylpropylene, and naphthylethylene.

The term “(C₅-C₁₄)heteroaryl-(C₁-C₁₀)alkylene” refers to a divalentalkylene wherein one or more hydrogen atoms in the C₁-C₁₀ alkylene groupis replaced a (C₃-C₁₄)heteroaryl group. Examples of(C₃-C₁₄)heteroaryl-(C₁-C₁₀)alkylene groups include without limitation1-pyridylbutylene, quinolinyl-2-butylene and1-pyridyl-2-methylpropylene.

The term “—(C₅-C₁₄)heteroarylene-(C₁-C₁₀)alkylene-” refers to a divalentalkylene wherein one or more hydrogen atoms in the C₁-C₁₀ alkylene groupis replaced a (C₃-C₁₄)heteroaryl group and wherein one of the hydrogensor one of the heteroatoms of the (C₃-C₁₄)heteroaryl group is bonded toanother group, for example, a (C₁-C₁₀)alkyl group.

A “benzyl” is

while the term “benzylene” denotes a divalent benzyl moiety that isrepresented by the following structure

A halogen refers to chlorine, bromine, fluorine, or iodine.

The definition of each expression, e.g. alkyl, m, n, and the like, whenit occurs more than once in any structure, is intended to be independentof its definition elsewhere in the same structure.

The terms triflyl, tosyl, mesyl, and nonaflyl refer totrifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, andnonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain the groups, respectively. Theabbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations.

Certain compounds contained in the compositions may exist in particulargeometric or stereoisomeric forms. In addition, compounds may also beoptically active. The compounds may also include cis- and trans-isomers,R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, theracemic mixtures thereof, and other mixtures thereof. Additionalasymmetric carbon atoms may be present in a substituent such as an alkylgroup. If, for instance, a particular enantiomer of compound is desired,it may be prepared by asymmetric synthesis, or by derivation with achiral auxiliary, where the resulting diastereomeric mixture isseparated and the auxiliary group cleaved to provide the pure desiredenantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 3^(rd) ed.; Wiley: New York,1999).

Unless otherwise indicated, “stereoisomer” means one stereoisomer of acompound that is substantially free of other stereoisomers of thatcompound. Thus, a stereomerically pure compound having one chiral centerwill be substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, for example greater than about 90%by weight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name giventhat structure, then the depicted structure controls. Additionally, ifthe stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

As described above, the present invention relates to compounds accordingto Formula I.

For Formula I compounds variable A is (CHR¹)_(m) or C(O) and W isselected from the group consisting of —C(O)—(CH₂)_(p)—;—C(O)[—CH₂—CH₂—O]_(n)—, —[CH₂—CH₂—O]_(n)—(CH₂)₂—,—C(O)—[CH(R³)_(t)]_(q)—, —(CH₂)_(m)—O—(CH₂)_(n)—,—(CH₂)_(m)—S—(CH₂)_(n)—, —(CH₂)_(m)—S(O)—(CH₂)_(n)—,—(CH₂)_(m)—S(O)₂—(CH₂)_(n)—, and —(CH₂)_(m)—NR_(a)—(CH₂)_(n)—.

Variable Y in Formula I is selected from —NH—, —NR²—, or

and X is group selected from —(C₁-C₁₀)alkylene-(C₃-C₁₀)arylene,—(C₃-C₁₀)arylene, —(C₃-C₁₀)arylene-(C₁-C₁₀)alkylene-, phenylene,—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkylene, —(C₃-C₁₀)cycloalkylene, or—(C₃-C₁₀)cycloalkylene-(C₁-C₁₀)alkylene-. For certain Formula Icompounds X is a —(C₃-C₁₀)arylene, such as a phenylene group.

Substituent groups R¹ and R² in Formula I are each independentlyselected from H, —(C₁-C₁₀)alkyl, —C(O)—(C₁-C₁₀)alkyl, benzyl,—(C₃-C₁₀)cycloalkyl, or —(C₃-C₁₀)aryl, while groups R^(a) and R^(b) areeach independently selected from the group consisting of H, —OH,—(C₁-C₁₀)alkyl, —[CH₂—CH₂—O]_(n)—(CH₂)₂-T, —C(O)—(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—Z, benzyl,—(C₃-C₁₀)cycloalkyl, —(C₃-C₁₀)aryl-(C₁-C₁₀)alkylene, —(C₃-C₁₀)aryl,halo-(C₁-C₁₀)alkyl, hydroxy-(C₁-C₁₀)alkyl, —NH—(C₁-C₁₀)alkyl, and—(C₁-C₁₀)alkylene-NR^(d)R^(e)—. For certain Formula I compounds R^(a)and R^(b) together with the nitrogen to which they are bonded form a(C₃-C₆)-heteroaryl or (C₃-C₆)-heterocycloalkyl that can further compriseone or more heteroatoms selected from N, S, or O.

Z in Formula I can be selected from —OH, —O(C₁-C₁₀)alkyl,

substituent R^(c) is selected from —OH, —O(C₁-C₁₀)alkyl, -Obenzyl,—O(C₃-C₁₀)cycloalkyl, —O(C₃-C₁₀)aryl, —O—(C₁-C₁₀)alkylene-(C₃-C₁₀)aryl,or —O—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkyl and R³ is selected from H,halogen, —OH, —NH₂, —(CH₂)_(p)—COOH, or —(CH₂)_(p)—NH₂.

In Formula I T is selected from —H, —OH, —COOH, or —NR^(d)R^(e) and whenT is —NR^(d)R^(e), substituent groups R^(d) and R^(e) are eachindependently selected from H, bond, —OH, —(C₁-C₁₀)alkyl, or—(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene;

Subscripts m, n, p, q, t and r are each independently 0, 1, 2, 3, 4, 5,6, 7, 8 9, or 10; and the chelator group D is

For Formula I compounds any alkyl, alkylene, aryl, arylene, heteroaryl,heteroarylene, cycloalkyl, cycloalkylene, heterocycloalkyl, orheterocycloalkylene is optionally substituted with 1, 2, or 3substituent groups selected from the group consisting of —(C₁-C₁₀)alkyl,—(C₁-C₁₀)haloalkyl, —(C₁-C₁₀) aminoalkyl, —(C₁-C₁₀)alkylene-COOH,—(C₁-C₁₀)hydroxyalkyl, —OH, halogen, —NH₂, —COOH, —C(O)—(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—X, —NH—(C₁-C₁₀)alkyl,and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, and —NR^(d)R^(e).

In one aspect for an inventive Formula I compound X is phenylene,subscript “r” is 1 and D is

the metal chelator DOTA. Pursuant to these qualifications is a FormulaII compound as illustrated below. For certain Formula II compounds A is(CHR¹)_(m), W is a C(O)—(CH₂)₇— or —C(O)—(CH₂)₁₀— group and Y is

In one embodiment, A is (CHR¹)_(m) with R¹ being a hydrogen and m is 2.For certain Formula II compounds R^(a) and R^(b) together with thenitrogen to which they are bonded form a (C₃-C₆)-heterocycloalkylselected from piperidine, piperazine, morpholine, thiomorpholine,isothiazolidine, isoxazolidine, pyrrolidine, immidazolidine,thiazolidine or oxazolidine. For some Formula II compounds R^(a) is —Hand R^(b) is

with R^(d) and R^(e) each independently being a—(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene, for example, R^(d) and R^(e) areeach independently

An illustrative Formula II compound that comports with the abovedefinition is illustrated below:

Other exemplary Formula I or Formula II compounds include withoutlimitation compounds mentioned in Table 1 below. While some exemplarycompounds are depicted with stereochemistry, it should be understoodthat the invention includes all possible stereoisomers, such asdiastereomers, of the compounds.

TABLE 1

Pharmaceutically acceptable salts and/or solvates of the inventiveFormula I and Formula II compounds illustrated above are also within thescope of the present invention. In some embodiments, the chelator group,for example, the DOTA group is not complexed with a radionuclide. WhenDOTA is uncomplexed the carboxylic acid groups of the DOTA group can bein the form of a free acid, or in the form of a salt. The freecarboxylic acid groups can also be esterified to obtain the prodrug formof Formula I or Formula II compounds. Suitable ester prodrugs includevarious alkyl esters, including saturated and unsaturated C₈ to C₁₈fatty acids.

The inventive compounds are glutamate-urea-lysine (GUL-) orglutamate-urea-glutamate (GUG) analogs in which a chelator group isconjugated to the GUL- or GUG-moiety via a linker.

As further discussed below, the length and chemical nature of the linkergroup is believed to influence the binding avidity of the inventivecompounds to the target tissue. Thus, radionuclide complexes of FormulaI or Formula II compounds having apiperazine-triazinyl-p-aminobenzyl-DOTA moiety within the linker wereobserved to concentrate to a greater extent in tumor tissue thannon-tumor tissue, such as blood, heart, lungs, liver, spleen, stomach,large and small intestines, testes, skeletal muscle, bone, brain, andadipose tissue.

These compounds, moreover, were rapidly cleared by the kidneys. It wasobserved that over a period of 96 hours, thepiperazine-triazinyl-p-aminobenzyl-DOTA containing compounds initiallyconcentrated in the kidneys but at longer intervals of time were rapidlycleared by the kidneys. For example, Formula I or Formula II compoundsconcentrate to a greater extent in the kidneys than tumor at 4 hourspost administration. However, the concentration of the inventivecompounds in tumor did not change as a function of time. Thus, the tumorconcentration of Formula I or Formula II compounds at 4 hours postadministration is similar to their tumor concentration at 24 hours and96 hours post administration.

Depending on whether the Formula I or Formula II compounds are to beused as radioimaging agents or radio pharmaceuticals, differentradionuclides are complexed to the compounds. Illustrative of suitableradionuclides are those selected from the actinide series, lanthanideseries and radionuclides of transition metals, for example, ¹¹¹In, ⁹⁰Y,⁶⁸Ga, ⁶⁴Cu, ¹⁵³Gd, ¹⁵⁵Gd, ¹⁵⁷Gd, ⁵⁹Fe, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁵⁵Co, ⁶⁷Cu,¹⁶⁵Dy, ¹⁶⁶Ho, ¹⁹²Ir, ²²³Ra, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁰⁵Rh, ²¹²Pb, ²¹³Pb, ¹⁴⁹Tb,²²⁷Th ¹⁵³Sm, ⁸⁹Sr, ^(117m)Sn, ¹⁶⁹Yb, ⁹⁰Y, ⁸⁶Y, ⁸⁹Zr and ¹⁷⁷Lu.

Illustrative of Formula I or Formula II compounds complexed to anexemplary radionuclide ¹⁷⁷Lu are those illustrated below in Table 2.

TABLE 2

or a pharmaceutically acceptable salt or solvate thereof.

FIG. 1 and FIG. 2 illustrate results of a bio-distribution study of aGUL-[piperazine-triazinyl-p-aminobenzyl]-DOTA-¹⁷⁷Lu complexes accordingto Formula I or Formula II in LNCap xenograft mice, while FIG. 3illustrates results of a bio-distribution study of a GUL-[alkylenethiourea]-DOTA-¹⁷⁷Lu complex in LNCap xenograft mice.

As illustrated by the bar graphs in these figures, complexes (A), (B)and (C) concentrate in kidneys and tumor to a greater extent than othertissues. In fact, at 4 hours post administration, the observedconcentration for each complex (A), (B) and (C) was greater in kidneysthan in tumor. As illustrated by FIGS. 1-3, however, at 24 hours and 96hours post administration the concentration of the inventiveGUL-[piperazine-triazinyl-p-aminobenzyl]-DOTA-¹⁷⁷Lu complexes (A) and(B) in LNCap tumor cells remained unchanged while the concentration ofcomplex (C) used as a control decreases in LNCAP tumor cells at theselonger intervals of time.

These results were unexpected and suggest a greater ability forradionuclide complexes of Formula I or Formula II compounds toconcentrate in tumor cells. Moreover, as illustrated in FIGS. 1 and 2,inventive complexes (A) and (B) are rapidly cleared from the kidneys.Because radionuclide complexes of Formula I or Formula II compoundsconcentrate in tumor and are rapidly cleared by the kidneys,radionuclide complexes of Formula I or Formula II compounds arecandidate therapeutics for treating cancer, for example, prostatecancer.

Further confirmation that the inventive complexes concentrate in LNCaPtumors but are more rapidly cleared from other tissues including kidneyspost administration to LNCaP tumor bearing mice was obtained in aseparate extended biodistribution study using theGUL-[piperazine-triazinyl-p-aminobenzyl]-DOTA-¹⁷⁷Lu complex (D),illustrated below.

As illustrated by the bar graph in FIG. 4, the inventive complexconcentrates to a greater extent in kidneys and tumor than other tissuesat shorter time intervals post administration. For instance, there is agradual increase in the concentration of complex (D) in kidneys andtumor as a function of time over the first eight hours postadministration. At longer time intervals, for example between 24 hoursto 96 hours however, the concentration of complex (D) in kidneydecreases while there is no observable change in the concentration ofcomplex (D) in tumor.

To further investigate the pharmacokinetics of tumor retention and renalclearance, the biodistribution study was extended to 3 weeks. Tissueanalysis at 1 week post administration of complex (D) indicated noappreciable change in the intracellular concentration of this complex inLNCaP tumor cells. The intrarenal concentration at 1 week postadministration of complex (D) is significantly lower than the intrarenalconcentration of complex (D) at earlier time intervals, for example,within eight hours post administration.

At 3 weeks post administration, tissue analysis indicates a decrease inthe intratumoral concentration of complex (D). However, the decrease inthe concentration of the inventive complex in tumor is less compared tothe decrease in the intrarenal concentration of complex (D). Asmentioned above, the extended biodistribution study confirmed initialobservations that within the same period of time there is a more rapiddecrease in the concentration of complex (D) from the kidneys thantumor. Taken together, these results illustrate a greater affinity forthe inventive radionuclide complexes that comport with Formula I orFormula II for tumor cells than non-tumor tissue, such as blood, heart,lungs, liver, spleen, stomach, large and small intestines, testes,skeletal muscle, bone, brain, and adipose tissue. Accordingly, Formula Iand Formula II compounds are candidate therapeutic or imaging agents forselectively imaging LNCap tumor cells.

The compounds of Formula I or Formula II were screened in a humanprostate cancer cell competitive binding assay using PSMA positive (+),LnCap cells against the known inhibitor of PSMA,(7S,14S,18S)-7-amino-1-(1-(carboxymethyl)-1H-imidazol-2-yl)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylicacid (^(99m)Tc-MIP-1405), and IC₅₀ values were calculated.

Briefly, LNCaP human prostate cancer cells were obtained from AmericanType Culture Collection, Rockville, Md. LNCaP cells were maintained inRPMI-1640 medium supplemented with 10% fetal bovine serum (FBS). Bindingof the radiolabeled compound and competition with cold derivatives toLNCaP cells was performed according to published methods. Cells wereplated in 12-well plates at approximately 4×10⁵ cells/well and incubatedfor 48 hours in a humidified incubator at 37° C./5% carbon dioxide priorto addition of compound. Solutions of the Formula I or Formula IIcompounds were prepared and diluted in serum-free cell culture mediumcontaining 0.5% bovine serum albumin (BSA) in combination with 3 nM^(99m)Tc-MIP-1405 (known inhibitor). Total binding was determined byincubating ^(99m)Tc-MIP-1405 without test compound. Plates wereincubated at room temperature for 1 hour. Cells were removed from theplates and transferred to eppendorff tubes. Samples weremicrocentrifuged for 15 seconds at 10K×g. The medium was aspirated andthe pellet was washed twice by dispersal in fresh assay medium followedby microcentrifugation. Cell binding of ^(99m)Tc-MIP-1405 was determinedby counting the cell pellet in an automated gamma counter. Table 3illustrates the IC₅₀ values of representative Formula II non-radioactive¹⁷⁵Lu complexes.

TABLE 3 IC₅₀ Complex (nM)

 7.2

 11

 20

 6.7

 47

 1.3

 13

 10

 40

129

 90

121

 22

 20

 17

 6

As illustrated above, Formula I and Formula II compounds of theinvention bind to PSMA expressed on the surface of prostate cancer cellswith IC₅₀ values in the nanomolar range. The inventive compounds,therefore, are candidate radiotherapeutic agents for inhibiting thegrowth of prostate cancer tumor. Please note that in some structuresdepicted above and elsewhere in this disclosure there may or may not bedashed or solid lines showing putative interactions between certainfunctional groups and a metal radionuclide. These depictions are merelyillustrative of possible bonding interactions, but by no means shouldthey be interpreted as the only possible or actual metal-ligandinteraction(s) present for the particular metal complex depicted. Forexample, it is possible, perhaps even probably, that one or more of themacrocylic aza groups are contributing to the overall bondinginteractions between the metal ion and the chelating ligand.

FIG. 5 illustrates the in vivo efficacy of an exemplary lutetium complexof the invention to inhibit the growth of LNCaP tumors in mice. Arrestof tumor growth was determined by administering 450 μCi of the lutetiumcomplex of(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid to each mouse in the study group. Mice in the contro group wereadministered saline. Tumor volumes in the test and control group of micewere measured twice weekly. Tumor volumes of mice receiving the lutetiumcomplex according to the invention, were significantly lower than thetumor volumes of mice in the control group.

In fact, as illustrated in FIG. 5, LNCaP tumor volumes of mice in thetest group were observed to decrease to values lower than the tumorvolume at the start of the study upon administration of the inventivecomplex. In contrast, there was an increase in the volume of LNCaPtumors in mice receiving saline. These observations indicate thatradionuclide complexes of the inventive Formula I and Formula IIcompounds are effective at arresting the growth of prostate cancer invivo.

According to another embodiment of the invention, radiometal complexesof Formula I and Formula II compounds were used for imaging prostatecancer and accompanying metastasis in a subject. Briefly, ⁶⁸Ga wascomplexed to(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioic acid and the resultant complex was administered to asubject having prostate cancer. The subject was then imaged at 1 hourand 3 hours post administration of the inventive ⁶⁸Ga complex using, forexample, a ⁶⁸Ga-PSMA PET/CT scanner. As illustrated in FIG. 6, PSMAspecific lesions were detected in the lymph nodes and bone, in additionto the prostate tissue itself. Some imaging agent was also visible inthe subject's bladder at hour 1, which was cleared by the 3-hour scan.The radiographic image in FIG. 6 further indicates that the inventivecomplex accumulates in the lacrimal and salivary glands, kidney, liver,and urinary bladder. Overall, this imaging study supports the use ofradiometal complexes of the inventive compounds as suitable agents forradioimaging of cancers, such as prostate cancer.

Because Formula I and Formula II compounds and their radionuclidecomplexes can have one or more chiral centers, the present inventionencompasses both enantiomers, as well as all of the diasteroisomers.Moreover, both L and D-forms of the natural amino acids can be used forsynthesizing the Formula I and Formula II compounds. That is, thepresent invention encompasses stereoisomers, tautomers, and prodrugs ofFormula I and Formula II compounds and their radionuclide complexes.

As noted above, radinuclide complexes of Formula I or Formula IIcompounds may contain one or more radionuclides which are suitable foruse as radio-imaging agents or as radio-therapeutics for the treatmentof diseases associated with the uncontrolled and rapid proliferation ofcells, for example, PSMA expressing prostate cancer cells. Accordingly,in one embodiment, a pharmaceutical composition is provided including acomplex that includes a metal and a compound of Formula I or Formula II,a salt, solvate, stereoisomer, or tautomer thereof, and apharmaceutically acceptable carrier.

In general, metal complexes of a Formula I or a Formula II compound orpharmaceutical compositions thereof, may be administered orally, or viaa parenteral route, usually by injection. Parenteral routes include, butare not limited to, intravenous, intramuscular, intraarterial,intrathecal, intracapsular, intraorbital, intracardiac, intradermal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intraarticulare, subcapsular, subarachnoid, intraspinal and intrastemalinjection and infusion. In some embodiments, the compound, orpharmaceutical composition thereof, is administered orally. Suchcompositions may take the form of tablets, pills, capsules, semisolids,powders, solutions, suspensions, elixirs, aerosols, or any otherappropriate compositions.

According to another aspect, a pharmaceutical composition is provided,which is suitable for in vivo imaging and radiotherapy. Suitablepharmaceutical compositions may contain a radio imaging agent, or aradiotherapeutic agent that has a radionuclide either as an element,i.e. radioactive iodine, or a radioactive metal chelate complex of thecompound of Formula I or Formula II in an amount sufficient for imaging,together with a pharmaceutically acceptable radiological vehicle. Theradiological vehicle should be suitable for injection or aspiration,such as human serum albumin; aqueous buffer solutions, e.g.,tris(hydromethyl) aminomethane (and its salts), phosphate, citrate,bicarbonate, etc; sterile water; physiological saline; and balancedionic solutions containing chloride and or dicarbonate salts or normalblood plasma cations such as calcium, potassium, sodium, and magnesium.

The concentration of the imaging agent or the therapeutic agent in theradiological vehicle should be sufficient to provide satisfactoryimaging. For example, when using an aqueous solution, the dosage isabout 1.0 to 50 millicuries. The actual dose administered to a patientfor imaging or therapeutic purposes, however, is determined by thephysician administering treatment. The imaging agent or therapeuticagent should be administered so as to remain in the patient for about 1to 24 hours, although both longer and shorter time periods areacceptable. Therefore, convenient ampoules containing 1 to 10 mL ofaqueous solution may be prepared.

Imaging may be carried out in the normal manner, for example byinjecting a sufficient amount of the imaging composition to provideadequate imaging and then scanning with a suitable machine, such as agamma camera. In certain embodiments, a method of imaging a region in apatient, for example, imaging one or more tissues that expressprostate-specific membrane antigen (PSMA) includes the steps of: (i)administering to a patient a diagnostically effective amount of aFormula I, Formula II or Formula III compound complexed with aradionuclide so as to contact the one or more tissues expressing PSMAwith a radionuclide complex of a Formula I, Formula II or Formula IIIcompound; and (ii) recording a radiographicimage of the one or moretissues. In one embodiment the tissue imaged is a prostate tissue or aprostate cancer tissue. According to the inventive methodology, imagingcan be carried out by administering to a patient a diagnosticallyeffective amount of a Formula I compound complexed to a radionuclide, aFormula II compound complexed to a radionuclide or a Formula IIIcompound complexed to a radionuclide, or a pharmaceutically acceptablesalt or solvate of the inventive complexes.

In one embodiment, therefore, imaging is carried out using aradionuclide complex of a Formula compound

In Formula III, G is

is selected from —NH—(C₁-C₁₀)alkylene-, —NH—(C₁-C₁₀)alkylene-C(O)—,—C(O)—(C₁-C₁₀)alkylene-, —C(O)—(C₁-C₁₀)alkylene-C(O)— or

and variables R^(a) and R^(b) are each independently selected from thegroup consisting of H, —OH, —(C₁-C₁₀)alkyl, —[CH₂—CH₂—O]_(n)—(CH₂)₂-T,—C(O)—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—Z,benzyl, —(C₃-C₁₀)cycloalkyl, —(C₃-C₁₀)aryl-(C₁-C₁₀)alkylene,—(C₃-C₁₀)aryl, halo-(C₁-C₁₀)alkyl, hydroxy-(C₁-C₁₀)alkyl,—NH—(C₁-C₁₀)alkyl, and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, or R^(a) andR^(b) together with the nitrogen to which they are bonded form a(C₃-C₆)-heteroaryl or (C₃-C₆)-heterocycloalkyl that can further compriseone or more heteroatoms selected from N, S, or O.

Z in Formula III is selected from —OH, —O(C₁-C₁₀)alkyl,

while R^(d) and R^(e) are each independently selected from H, bond, —OH,—(C₁-C₁₀)alkyl, or —(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene. Subscript “n”is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10. ForFormula III compounds, any alkyl, alkylene, aryl, arylene, heteroaryl,heteroarylene, cycloalkyl, cycloalkylene, heterocycloalkyl, orheterocycloalkylene is optionally substituted with 1, 2, or 3substituent groups selected from the group consisting of —(C₁-C₁₀)alkyl,—(C₁-C₁₀)haloalkyl, —(C₁-C₁₀) aminoalkyl, —(C₁-C₁₀)alkylene-COOH,—(C₁-C₁₀)hydroxyalkyl, —NH₂, —COOH, —C(O)—(C₁-C₁₀)alkyl,—(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—X, —NH—(C₁-C₁₀)alkyl,and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, and —NR^(d)R^(e).

The metal used to form the complex is a radionuclide selected from¹¹¹In, ⁹⁰Y, ⁶⁸Ga, ⁶⁴Cu, ¹⁵³Gd, ¹⁵⁵Gd, ¹⁵⁷Gd, ⁵⁹Fe, ²²⁵Ac, ²¹²Bi, ²¹³Bi,⁵⁵Co, ⁶⁷Cu, ¹⁶⁵Dy, ¹⁶⁶Ho, ¹⁹²Ir, ²²³Ra, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁰⁵Rh, ²¹²Pb,²¹³Pb, ¹⁴⁹Tb, ²²⁷Th, ¹⁵³Sm, ⁸⁹Sr, ^(177n)Sn, ¹⁶⁹Yb, ⁹⁰Y, ⁸⁶Y, ⁸⁹Zr and¹⁷⁷Lu.

The amount of a Formula I, Formula II or Formula III compound, or aformulation comprising a complex of a radiometal and a compoundaccording to Formula I or Formula II, or its salt, solvate,stereoisomer, or tautomer that is administered to a patient depends onseveral physiological factors that are routinely used by the physician,including the nature of imaging to be carried out, tissue to be targetedfor imaging and the body weight and medical history of the patient to beimaged.

Also described is a method for treating a patient diagnosed with cancerby administering to such a patient a therapeutically effective amount ofa prostate-specific membrane antigen (PSMA) binding complex comprising atriazinylene linker. In one embodiment of this methodology, theprostate-specific membrane antigen (PSMA) binding complex comprising atriazinylene linker is a Formula I, Formula II or Formula III compoundcomplexed to a radionuclide, or a pharmaceutically acceptable salt orsolvate of the complex. Radionuclide complexes of Formula I, Formula IIand Formula III compounds, as described above, are preferentiallyretained in PSMA-expressing tumor tissue than non-PSMA expressingtissues such as kidney, liver, spleen, heart, blood, lungs, muscle,bone, large intestine, small intestine, brain, or fat. In addition toprostate cancer, radionuclide complexes of Formula I or Formula IIcompounds are also candidate therapeutics for treating breast cancer,colon cancer, brain cancer, lung cancer, liver cancer or kidney cancer.

The present invention, thus generally described, will be understood morereadily by reference to the following examples, which are provided byway of illustration and are not intended to be limiting of the presentinvention.

Examples General Protocol for Cell Culture

Human prostate cancer LNCaP cells were obtained from the American TypeCulture Collection. Cell culture supplies were from Invitrogen unlessotherwise noted. LNCaP cells were maintained in RPMI-1640 mediumsupplemented with 10% fetal bovine serum (Hyclone), 4 mM L-glutamine, 1mM sodium pyruvate, 10 mM hepes, 2.5 mg/mL D-glucose, and 50 μg/mLgentamicin in a humidified incubator at 37° C./5% CO₂. Cells wereremoved from flasks for passage, inoculation of mice or for transfer to12-well assay plates by incubating them with 0.25% trypsin/EDTA.

General Protocol for Competitive Binding

The ability of non-radioactive lutetium containing PSMA inhibitors tocompete with^(99m)Tc-((7S,14S,18S)-7-amino-1-(1-(carboxymethyl)-1H-imidazol-2-yl)-2-((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylicacid) for binding to PSMA in LNCaP cells was examined. LNCaP cells(4×10⁵ cells/well in 12-well plates in triplicate) were incubated for 1hour with 3 nM of the^(99m)Tc-complex in RPMI medium containing 0.5% BSAin the presence of 1-10,000 nM test compounds. Cells were removed toEppendorf tubes by gently pipetting, washed twice with RPMI+0.5% BSA andcounted.

Mouse Studies

All animal studies were approved by the Institute for Animal Care andUse Committee in accordance with the guidelines set forth by the U.S.Public Health Service Policy on Humane Care and Use of LaboratoryAnimals. Mice were housed under standard conditions in approvedfacilities with 12 hour light/dark cycles and given food and water adlibitum. Male athymic NCr-nu/nu mice were purchased from Taconic. Forinoculation in mice, LNCaP cells were resuspended at 10⁷ cells/ml in a1:1 mixture of cell culture medium: Matrigel (BD Biosciences). Eachmouse was injected in the right flank with 0.25 ml of the cellsuspension. Mice were used for tissue distribution studies when thetumors reached approximately 100-400 mm³.

Tissue Distribution

A quantitative analysis of the tissue distribution of ¹⁷⁷Lu-labeledcompounds was performed in separate groups of male NCr-nu/nu micebearing LNCaP cell xenografts. The compounds were administered via thetail vein as a bolus injection (approximately 10 μCi/mouse) in aconstant volume of 0.05 mL. The animals (n=5/time point) were euthanizedby asphyxiation with carbon dioxide at the indicated time points afterinjection. Tissues, for example, blood, heart, lungs, liver, spleen,kidneys, stomach, large and small intestines (with contents), testes,skeletal muscle, bone, brain, adipose, and tumor were dissected,excised, weighed wet, and counted in an automated γ-counter. Tissuetime-radioactivity levels were expressed as percent injected dose pergram of tissue (% ID/g).

In Vivo Efficacy

Mice bearing LNCaP xenografts having an average volume of ˜100-500 mm³,were randomly assigned to a control group or a treatment group (n=10mice per group). Mice in the control group were administered salinewhile mice in the test group received 450 μCi/mouse of ¹⁷⁷Lu-complex ofthe inventive Formula I or Formula II compound. Each animal wasadministered the test article intravenously in a volume of 0.05 mL.Tumor dimensions were measured twice weekly with digital calipers andtumor volumes were calculated using the formula (4/3×Π×width²×length)/6.Measurements were made until tumor volumes in the vehicle group reachedthe maximum allowed by IACUC guidelines (1,500 mm³).

General Synthetic Methods.

General procedure for the synthesis of Formula I compounds and forcomplexation of a Formula I compound with a radionuclide are described.While a protocol for complexing lutetium to a Formula I compound isexemplified below, it is to be understood that a similar syntheticprocedure can be followed for complexing other radionuclides. Therefore,while lutetium may specifically be shown in various examples describedbelow, complexes with other radionuclides such as In, Y, Zr, Ga, Lu, Cu,Gd, Ac Fe, Bi Co, Dy Ho, Ir, Ra, Re, Rh, Sr or Sm are within the scopeof the present invention. Additionally, it is to be understood thatvarious isotopes of these elements may be complexed, for example, ¹¹¹In,⁹⁰Y, ⁶⁸Ga, ⁶⁴Cu, ¹⁵³Gd, ¹⁵⁵Gd, ¹⁵⁷Gd, ⁵⁹Fe, ²²⁵Ac, ²¹²Bi, ²¹³Bi, ⁵⁵Co,⁶⁷Cu, ¹⁶⁵Dy, ¹⁶⁶Ho, ¹⁹²Ir, ²²³Ra, ¹⁸⁶Re, ¹⁸⁸Re, ¹⁰⁵Rh, ²¹²Pb, ²¹³Pb,¹⁴⁹Tb, ²²⁷Th, ¹⁵³Sm, ⁸⁹Sr, ^(177m)Sn, ¹⁶⁹Yb ⁹⁰Y, ⁸⁶Y, ⁸⁹Zr and ¹⁷⁷Lu.

General Experimental Conditions for the Formation of the LutetiumComplexes

The lutetium complexes of Formula I compounds were conveniently isolatedfrom the reactions that involve contacting commercially available LuCl₃with a compound according to Formula I. Briefly, a 10⁻⁶ M-10⁻⁴ Msolution of the desired Formula I or Formula II compound in an equalvolume mixture of 1:1 acetonitrile and phosphate buffer was contactedwith LuCl₃ in a sealed vial. The reaction mixture was heated at 100° C.for 30 to 45 minutes. Upon cooling, the reaction was analyzed forcompletion and purity by reverse-phase high pressure liquidchromatography (RP-HPLC) and if required was purified using RP-HPLC or aC18 Sep Pak column. The overall average yield of the lutetium complexedproduct following purification was in the range from about 20% to about99%. The radiochemical purity (RCP), after HPLC purification, however,was consistently ≧95%.

Initial results demonstrated radiolabeling of a Formula I or a FormulaII compound at concentrations as low as 10⁻⁶ M, the radiochemical yield(RCY) at this concentration of reagents was approximately ≦80%. Toachieve a higher RCY, greater than 95%, the reaction temperature andconcentration of reagents in the reaction mixture were increased to 10⁻⁴M.

A similar synthetic strategy was used to incorporate otherradionuclides. Moreover, the introduction of a radionuclide can be madeeither prior to deprotection of a Formula I or Formula II compound, orafter deprotecting a Formula I compound.

Synthesis of Exemplary Triazine-Piperazine Based Formula I, Formula II,or Formula III Compounds

Schemes A, B and C illustrate general synthetic protocols for exemplaryFormula I compounds. Briefly, p-aminobenzyl DOTA is contacted withcyanuric chloride followed by reaction of the resultant product with anamine. The product thus formed is then contacted with a GUG- orGUL-linker-piperazine moiety to obtain a Formula I compound.

Example 1:(2S)-2-(3-((1S)-1-carboxy-5-(8-((4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)octanamido)pentyl)ureido)pentanedioic acid lutetium complex

Step 1. (18S,22S)-tri-tert-butyl1-(9H-fluoren-9-yl)-3,12,20-trioxo-2-oxa-4,13,19,21-tetraazatetracosane-18,22,24-tricarboxylate

A solution of (S)-di-tert-butyl2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(1.9677 g, 4.03 mmol),8-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)octanoic acid (1.84 g, 4.84mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (EDCI; (0.770 g,4.03 mmol), HOBt (0.544 g, 4.03 mmol) and N,N-diisopropylethylamine(DIPEA; (2.0 mL)) in DCE (100 mL) was stirred at room temperature forovernight. The solvent was evaporated to give a residue, which waspurified by silica gel column chromatography (Biotage) using a mixtureof DCM/MeOH as the eluent to give (18S,22S)-tri-tert-butyl1-(9H-fluoren-9-yl)-3,12,20-trioxo-2-oxa-4,13,19,21-tetraazatetracosane-18,22,24-tricarboxylate(2.099 g, 61%) as a white solid. MS (ESI), 851.2 (M+H)⁺.

Step 2. (S)-di-tert-butyl2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate

To a solution of (18S,22S)-tri-tert-butyl1-(9H-fluoren-9-yl)-3,12,20-trioxo-2-oxa-4,13,19,21-tetraazatetracosane-18,22,24-tricarboxylate(1.983 mg, 2.333 mmol) in DMF (4.0 mL) was added piperidine (4.0 mL).The mixture was stirred at room temperature for 3 hrs following whichthe solvent was evaporated under reduce pressure to afford a residue,which was purified by column chromatography using a Biotage SP4 columnand gradient elution using 100% DCM to a 1:1 mixture of DCM:methanol asthe eluting solvent. The product(S)-di-tert-butyl-2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(1.039 mg, 71%), thus obtained was characterized using ¹H NMR and massesspectrometry. ¹H NMR (400 MHz, DMSO-d₆) 7.71 (t, J=5.2 Hz, 1H), 6.29 (d,J=8.0 Hz, 1H), 6.25 (d, J=8.4 Hz, 1H), 5.74 (brs, 2H), 4.05-3.91 (m,2H), 3.01-2.88 (m, 2H), 2.63 (t, J=6.8 Hz, 2H), 2.20-1.22 (m, 49H); MS(ESI), 629.3 (M+H)⁺.

Step 3.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(dimethylamino)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (67.8 mg, 0.080 mmol)and cyanuric chloride (14.7 mg, 0.080 mmol) in DCM (4.0 mL) was addedDIPEA (0.10 mL). This solution was stirred at room temperature for 3hrs, following which the solvent was removed under a stream of nitrogento give a residue. To a DMSO (4.0 mL) solution of the residue was added(S)-di-tert-butyl2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(50.3 mg, 0.08 mmol) and K₂CO₃ (100 mg). The suspension was stirred atroom temperature for about 2 hrs and then a tetrahydrofuran solution ofdimethylamine (0.3 mL, 2.0 M in THF) was added to the reaction mixture.After stirring at room temperature continuously for 16 hrs, the reactionmixture was lyophilized to afford the crude triazine intermediate. Thecrude product was deprotected by the addition of TFA (4.0 mL) and DCM(1.0 mL) and stirring the reaction mixture at room temperature for 4hours. Removal of the solvent using a stream of nitrogen gas gave aresidue, which was purified using Biotage SP4 via C18 cartridge to give(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(dimethylamino)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid (67 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) 07.83-7.60 (m,3H), 7.17 (d, J=8.0 Hz, 2H), 6.32 (d, J=8.0 Hz, 1H), 6.28 (d, J=8.4 Hz,1H), 4.10-1.27 (m, 61H); MS (ESI), 1091.4 (M+H)⁺.

Step 4.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(dimethylamino)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(dimethylamino)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid (5.7 mg, 0.00522 mmol) was added LuCl₃ (1.46 mL of a 0.00357mmol/mL, 0.00522 mmol) and acetonitrile (0.50 mL). The reaction mixturewas heated at 95° C. for 1 hour and then lyophilized to give(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(dimethylamino)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid lutetium complex (6.2 mg) as a white solid. MS(ESI), 1263.0 (M+H)⁺.

Example 2.(S)-2-(3-((S)-1-Carboxy-5-(8-((4-(piperidin-1-yl)-6-((4-(((S)-1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)amino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((S)-1-carboxy-5-(8-(4-(piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL). This reaction mixture was stirred at roomtemperature for 2 hours following which the solvent was removed using astream of nitrogen to give a residue. The residue thus obtained wasdissolved in DMSO (4.0 mL) and (S)-di-tert-butyl2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(31.4 mg, 0.05 mmol) and K₂CO₃ (100 mg) were added. The suspension wasstirred at room temperature for 2 hrs and then piperidine (0.10 mL) wasadded. The reaction mixture was stirred at room temperature for anadditional 14 hrs and then lyophilized to afford a triazineintermediate, which was deprotected by the addition of TFA (2.0 mL) inDCM (1.0 mL). Deprotection was carried out by stirring the reactionmixture at room temperature for 4 hours. Following deprotection, thesolvent was removed using a stream of nitrogen to give a residue, whichwas purified by Biotage SP4 using C18 cartridge to give pure(2S)-2-(3-((S)-1-carboxy-5-(8-(4-(piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid

(25.8 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) 7.75-7.60 (m, 3H),7.18 (d, J=7.2 Hz, 2H), 6.33 (d, J=7.6 Hz, 1H), 6.30 (d, J=8.0 Hz, 1H),4.12-1.24 (m, 65H); MS (ESI), 1131.2 (M+H)⁺.

Step 2.(2S)-2-(3-((S)-1-carboxy-5-(8-(4-(piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacidlutetium complex

To solid(2S)-2-(3-((S)-1-carboxy-5-(8-(4-(piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid (9.2 mg, 0.00814 mmol) was added LuCl₃ (1.60 mL, of a 0.00513mmol/mL, 0.0082 mmol) and acetonitrile (0.50 mL). The reaction mixturewas heated at 95° C. for 1 hour and then lyophilized to give(2S)-2-(3-((S)-1-carboxy-5-(8-(4-(piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid lutetium complex (9.4 mg) as a white solid. MS(ESI), 1302.2 (M+H)⁺.

Example 3.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholino-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholino-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL). The reaction was stirred at roomtemperature for 2 hours and the solvent was then removed using a streamof nitrogen to give a residue. The residue was dissolved in DMSO (4.0mL) and (S)-di-tert-butyl2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(31.4 mg, 0.05 mmol) and K₂CO₃ (100 mg) were then added to the DMSOsolution. The suspension was stirred at room temperature for 2 hoursfollowing which morpholine (0.10 mL) was added and the reaction mixturewas stirred at room temperature for an additional 14 hours. The reactionmixture was lyophilized to afford a triazine intermediate to which wasadded TFA (2.0 mL) and DCM (1.0 mL). This mixture was stirred at roomtemperature for 4 hours to effect deprotection following which thesolvent was removed using a stream of nitrogen to give a residue of thecrude product. Purification was effected using a Biotage SP4 and a C18cartridge to give(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholino-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid (29.8 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) 7.75-7.65 (m,3H), 7.14 (m, 2H), 6.55 (m, 2H), 6.33 (d, J=8.0 Hz, 1H), 6.30 (d, J=8.4Hz, 1H), 4.10-1.27 (m, 61H); MS (ESI), 1133.2 (M+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholino-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholino-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid (10.4 mg, 0.0092 mmol) was added LuCl₃ (1.80 mL, 0.00513 mmol/mL,0.0092 mmol) and acetonitrile (0.50 mL). The reaction mixture was heatedat 95° C. for 1 hour and then lyophilized to to give(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-morpholino-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex (9.9 mg) as a white solid. MS (ESI), 1304.9(M+H)⁺.

Example 4.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-((4-carboxy-1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-6-(piperazin-1-yl)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-((4-carboxy-1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-6-(piperazin-1-yl)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL). The reaction was stirred at roomtemperature for 2 hrs. The solvent was then removed using a stream ofnitrogen to give a residue, which was dissolved in DMSO (4.0 mL) and(S)-di-tert-butyl2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(31.43 mg, 0.05 mmol) and K₂CO₃ (100 mg) were then added to the DMSOsolution. The resultant suspension was stirred at room temperature for 2hrs following which piperazine (100 mg) was added and stirring wascontinued at room temperature for an additional 16 hrs. The crudereaction was then lyophilized and the triazine intermediate thusobtained was added deprotected using TFA (2.0 mL) and DCM (1.0 mL).Deprotection was carried out by stirring the mixture at room temperatureovernight, following which the solvent was removed using a stream ofnitrogen to give a residue of the crude product which was purified byBiotage SP4 using a C18 cartridge to give(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-((4-carboxy-1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-6-(piperazin-1-yl)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid (18.9 mg) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) 8.85 (m, 2H),7.75-7.65 (m, 4H), 7.16 (m, 2H), 6.55 (m, 2H), 6.32 (d, J=8.8 Hz, 1H),6.29 (d, J=8.4 Hz, 1H), 4.11-1.23 (m, 61H); MS (ESI), 1132.2 (M+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-((4-carboxy-1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-6-(piperazin-1-yl)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-((4-carboxy-1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-6-(piperazin-1-yl)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid (7.8 mg, 0.0069 mmol) was added LuCl₃ (1.80 mL of a 0.00385mmol/mL, 0.0069 mmol and acetonitrile (0.5 mL). The reaction mixture washeated at 95° C. for 1 hour and then lyophilized to give(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-((4-carboxy-1,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-6-(piperazin-1-yl)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioicacid lutetium complex (8.3 mg) as a white solid. MS (ESI), 1303.6(M+H)⁺.

Example 5.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid

DIPEA (0.10 mL) was added to a solution ofp-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4 mg, 0.050 mmol) andcyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0 mL) and mixture wasstirred at room temperature for 2 hrs. The solvent was then removedusing a stream of nitrogen to give a residue, which was dissolved inDMSO (4.0 mL). (S)-di-tert-butyl2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-l-oxohexan-2-yl)ureido)pentanedioate(31.43 mg, 0.05 mmol) and K₂CO₃ (100 mg) were added to the DMSO solutionand the resultant suspension was stirred at room temperature for 2 hrsfollowing which 4-(piperidin-4-yl)butanoic acid (30 mg) was added. Afterstirring at room temperature for an additional 16 hours the reactionmixture was lyophilized to afford a triazine intermediate which wasdeprotected using TFA (2.0 mL) and DCM (1.0 mL). After stirring at roomtemperature overnight the solvent was removed using a stream of nitrogento give a residue of the titled crude. Purification was effected usingBiotage SP4 and a C18 cartridge to obtain(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid (18.8 mg) as a white solid. MS (ESI),608.8 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid (7.4 mg, 0.006086 mmol) was added LuCl₃(1.58 mL of a 0.00385 mmol/mL, 0.006086 mmol). The reaction mixture washeated at 95° C. for 1 hour and then lyophilized to give(2S)-2-(3-((1S)-1-carboxy-5-(8-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-(4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenylamino)-1,3,5-triazin-2-ylamino)octanamido)pentyl)ureido)pentanedioic acid lutetium complex (9.0 mg) as a whitesolid. MS (ESI), 1388.8 (M+H)⁺.

Example 6.((2S,2'S)-2,2′-(((((1S,1'S)-((8,8′-((6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(octanoyl))bis(azanediyl))bis(1-carboxypentane-5,1-diyl))bis(azanediyl))bis(carbonyl))bis(azanediyl))dipentanedioicacid lutetium complex

Step 1.((2S,2'S)-2,2′-(((((1S,1'S)-((8,8′-((6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(octanoyl))bis(azanediyl))bis(1-carboxypentane-5,1-diyl))bis(azanediyl))bis(carbonyl))bis(azanediyl))dipentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL) and the mixture stirred at roomtemperature for 2 hours. Following stirring, the solvent was removedusing a stream of nitrogen to give a residue. This residue was dissolvedin DMSO (4.0 mL) and (S)-di-tert-butyl2-(3-((S)-6-(8-aminooctanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(62.8 mg, 0.10 mmol) and K₂CO₃ (100 mg) were added to the resultant DMSOsolution. The suspension thus obtained was stirred at room temperaturefor 72 hours and then lyophilized to afford a triazine intermediatewhich was deprotected using TFA (4.0 mL) and DCM (1.0 mL). The TFA/DCMmixture was stirred at room temperature overnight following which thesolvent was removed using a stream of nitrogen to afford the titledcrude as a solid. The crude was purified by Biotage SP4 using C18cartridge to give pure((2S,2'S)-2,2′-(((((1S,1'S)-((8,8′-((6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(octanoyl))bis(azanediyl))bis(1-carboxypentane-5,1-diyl))bis(azanediyl))bis(carbonyl))bis(azanediyl))dipentanedioicacid (10.0 mg) as a white solid. MS (ESI), 753.2 (M/2+H)⁺.

Step 2.((2S,2'S)-2,2′-(((((1S,1'S)-((8,8′-((6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(octanoyl))bis(azanediyl))bis(1-carboxypentane-5,1-diyl))bis(azanediyl))bis(carbonyl))bis(azanediyl))dipentanedioicacid lutetium complex

To solid(((2S,2'S)-2,2′-(((((1S,1'S)-((8,8′-((6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(octanoyl))bis(azanediyl))bis(1-carboxypentane-5,1-diyl))bis(azanediyl))bis(carbonyl))bis(azanediyl))dipentanedioicacid (8.5 mg, 0.005646 mmol) was added LuCl₃ (1.47 mL of a 0.00385mmol/mL, 0.005646 mmol). The reaction mixture was heated at 70° C. for 1hour and then lyophilized to give (2S,2'S)-2,2′-(((((1S,1'S)-((8,8′-((6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(octanoyl))bis(azanediyl))bis(1-carboxypentane-5,1-diyl))bis(azanediyl))bis(carbonyl))bis(azanediyl))dipentanedioic acid lutetium complex (8.6 mg) as a white solid. MS(ESI), 1678.0 (M+H)⁺.

Example 7.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1. (S)-di-tert-butyl2-(3-((S)-6-(11-(4-((benzyloxy)carbonyl)piperazin-1-yl)undecanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate

A solution of (S)-di-tert-butyl2-(3-((S)-6-amino-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(1.023 g, 2.097 mmol),11-(4-((benzyloxy)carbonyl)piperazin-1-yl)undecanoic acid (0.77 g,1.9059 mmol), EDCI (0.40 g, 2.097 mmol), HOBt (0.27 g, 2.097 mmol) andDIPEA (1.0 mL) in dichloroethane (DCE; 25 mL) was stirred at roomtemperature overnight. The following day, the solvent was evaporated togive a residue, which was purified using Biotage column chromatographyand a mixture of DCM/MeOH as the eluant to give (S)-di-tert-butyl2-(3-((S)-6-(11-(4-((benzyloxy)carbonyl)piperazin-1-yl)undecanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(1.52 g, 91%) as a yellowish solid. MS (ESI), 874.3 (M+H)⁺.

Step 2. (S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate

To a solution of (S)-di-tert-butyl2-(3-((S)-6-(11-(4-((benzyloxy)carbonyl)piperazin-1-yl)undecanamido)-1-(tert-butoxy)-1-oxohexan-2-yl)ureido)pentanedioate(1.50 g, 1.72 mmol) and ammonium formate (1.0 g) in ethanol (60 mL) wasadded palladium on carbon (300 mg). The reaction mixture was stirred atroom temperature for overnight and filtered through a pad of celitefollowed by washing of the celite pad using ethyl acetate (EtOAc). Thesolvent was removed under reduced pressure and the residue dissolved indichloromethane (DCM). The DCM solution was washed using saturatedsodium bicarbonate and then partitioned to separate the organic layerfrom the aqueous layer. Concentration of the organic layer under reducedpressure afforded the titled product as a yellowish solid (1.2345 g, 97%yield). MS (ESI), 740.4 (M+H)⁺.

Step 3.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioic acid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL) and resultant mixture was stirred at roomtemperature for 2 hrs. Following stirring, the solvent was removed undera stream of nitrogen to give a residue, which was dissolved in DMSO (1.0mL) prior to the additon of (S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(34 mg, 0.05 mmol) and K₂CO₃ (50 mg). The resultant suspension wasstirred at room temperature for 2 hrs, following which a tetrahydrofuransolution of dimethylamine (0.2 mL, 2.0 M in THF) was added. Afteradditional stirring of the reaction mixture at room temperature for 16hours, the reaction was lyophilized to afford the crude triazineintermediate. Deprotection of the crude using TFA (2.0 mL) and DCM (1.0mL) was carried out at room temperature overnight. The following day,the solvent was removed under a stream of nitrogen to give a residue,which was purified by Biotage SP4 using C18 cartridge to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (24 mg) as a white solid. MS (ESI), 601.2 (M/2+H)⁺.

Step 4.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (9.4 mg, 0.00783 mmol) was added LuCl₃ (1.02 mL of a 0.00770mmol/mL, 0.00783 mmol). The reaction mixture was heated at 90° C. for 1hour and then lyophilized to to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex (11.1 mg) as a white solid. MS (ESI), 1373.7(M+H)⁺.

Example 8.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.((2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL) and the solution was stirred at roomtemperature for 2 hrs. The solvent was then removed using a stream ofnitrogen to give a residue, which was dissolved in DMSO (1.0 mL) priorto the addition of piperidine (4.25 mg, 0.05 mmol). The resultantsuspension was stirred at room temperature for 2 hours following which(S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) and K₂CO₃ (50 mg) were added to the DMSO solution.After additional stirring at room temperature for 16 hours and themixture was lyophilized to afford the crude triazine intermediate, whichwas deprotected using TFA (2.0 mL) and DCM (1.0 mL). Deprotection wascarried out by stirring the crude at room temperature overnight and thefollowing day the solvent was removed using a stream of nitrogen to givea residue which was purified by Biotage SP4 using a C18 cartridge togive((2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (22 mg) as a white solid. MS (ESI), 621.2 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (12.4 mg, 0.01 mmol) was added LuCl₃ (1.30 mL of a 0.00770 mmol/mL,0.01 mmol). The reaction mixture was heated at 90° C. for 1 hour andthen lyophilized to to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex (14.0 mg) as a white solid. MS (ESI), 1413.7(M+H)⁺.

Example 9.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid

To a DCM solution (2.0 mL) of p-NH2-Bn-DOTA-tetra(t-Bu-ester)(Macrocyclics) (42.4 mg, 0.050 mmol) and cyanuric chloride (9.2 mg,0.050 mmol) was added DIPEA (0.10 mL). After stirring at roomtemperature for 2 hours the solvent was removed under a stream ofnitrogen to give a residue, which was dissolved in DMSO (1.0 mL).Tert-butyl 3-(2-(2-aminoethoxy)ethoxy)propanoate (11.67 mg, 0.05 mmol)and K₂CO₃ (50 mg) were then added to the DMSO solution and the resultantsuspension was stirred at room temperature for 2 hours.(S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) was then added. After stirring for 16 hours thereaction mixture was lyophilized to afford the crude triazineintermediate which was deprotected using TFA (2.0 mL) and DCM (1.0 mL).Deprotection was carried out by stirring the crude at room temperatureovernight and the following day the solvent was removed using a streamof nitrogen to give a residue which was purified by Biotage SP4 usingC18 cartridge to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (29.4 mg) as a white solid. MS (ESI), 667.2 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (13.1 mg, 0.01 mmol) was added LuCl₃ (1.30 mL of a 0.00770 mmol/mL,0.01 mmol). The reaction mixture was heated at 90° C. for 1 hour andlyophilized to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((2-(2-(2-carboxyethoxy)ethoxy)ethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex (14.5 mg) as a white solid. MS (ESI), 1505.7(M+H)⁺.

Example 10.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((26-carboxy-3,6,9,12,15,18,21,24-octaoxahexacosyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((26-carboxy-3,6,9,12,15,18,21,24-octaoxahexacosyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL). The reaction was stirred at roomtemperature for 2 hrs and the solvent removed following stirring using astream of nitrogen. The residue thus obtained was dissolved in DMSO (1.0mL) and 1-amino-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-oic acid (22.1mg, 0.05 mmol) and K₂CO₃ (50 mg) were added to the DMSO solution. Theresultant suspension was stirred at room temperature for 2 hrs followingwhich (S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) was then added. After stirring for an additional 16hours at room temperature the crude reaction was lyophilized to affordthe triazine intermediate, which was deprotected overnight at roomtemperature using TFA (2.0 mL) and DCM (1.0 mL). The crude product waspurified by Biotage SP4 using a C18 cartridge to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((26-carboxy-3,6,9,12,15,18,21,24-octaoxahexacosyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (31.4 mg) as a white solid. MS (ESI), 799.3 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((26-carboxy-3,6,9,12,15,18,21,24-octaoxahexacosyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

LuCl₃ (0.69 mL of a 0.00770 mmol/mL, 0.00532 mmol) was added to solid(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((26-carboxy-3,6,9,12,15,18,21,24-octaoxahexacosyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (8.5 mg, 0.00532 mmol). The reaction mixture was heated at 90° C.for 1 hour and then lyophilized to to give2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-((26-carboxy-3,6,9,12,15,18,21,24-octaoxahexacosyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex (8.2 mg) as a white solid. MS (ESI), 885.2(M/2+H)⁺.

Example 11.(2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-1-carboxypentyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-1-carboxypentyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL). After stirring at room temperature for 2hours the solvent was removed using a stream of nitrogen gas to give aresidue. This residue was dissolved in DMSO (1.0 mL) and(S)-2-amino-6-(bis((1-(2-(tert-butoxy)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoicacid (26.7 mg, 0.05 mmol) and K₂CO₃ (50 mg) were then added. Theresultant suspension was stirred at room temperature overnight. Thefollowing day (S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) was added and the reaction mixture was stirred atroom temperature for an additional 24 hours. Lyophilization afforded thecrude triazine intermediate which was deprotected overnight at roomtemperature using TFA (3.0 mL) and DCM (1.0 mL). The deprotected crudefinal product was purified by Biotage SP4 using a C18 cartridge to give(2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-1-carboxypentyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid (41.5 mg) as a white solid. MS (ESI), 789.6 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-1-carboxypentyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-1-carboxypentyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid (16.3 mg, 0.0103 mmol) was added LuCl₃ (1.0 mL, 0.0103 mmol/mL,0.0103 mmol. The reaction mixture was heated at 90° C. for 1 hour andthen lyophilized to to give(2S)-2-(3-((1S)-5-(11-(4-(4-(((S)-5-(bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino)-1-carboxypentyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex (15.7 mg) as a white solid. MS (ESI), 875.6(M/2+H)⁺.

Example 12.(2S)-2-(3-((1S)-5-(11-(4-(4-(bis(carboxymethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-5-(11-(4-(4-(bis(carboxymethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid

To a DCM (2.0 mL) solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester)(Macrocyclics) (42.4 mg, 0.050 mmol) and cyanuric chloride (9.2 mg,0.050 mmol) was added DIPEA (0.10 mL) and resultant mixture was stirredat room temperature for 2 hrs. Removal of the solvent using a stream ofnitrogen gave a residue which was dissolved in DMSO (1.0 mL) prior tothe addition of di-tert-butyl 2,2′-azanediyldiacetate (24.5 mg, 0.10mmol) and K₂CO₃ (50 mg) were added. The resultant suspension was stirredat room temperature for overnight and the following day(S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) was added and the stirring continued at roomtemperature for 24 hours. Lyophilization of this suspension afforded thetriazine intermediate, which was deprotected at room temperatureovernight using TFA (3.0 mL) and DCM (1.0 mL). The deprotected crudeproduct was purified by Biotage SP4 using a C18 cartridge to give(2S)-2-(3-((1S)-5-(11-(4-(4-(bis(carboxymethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid (27.0 mg) as a white solid. MS (ESI), 645.2 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-5-(11-(4-(4-(bis(carboxymethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex

LuCl₃ (0.89 mL of a 0.0103 mmol/mL, 0.00915 mmol) was added to solidreagent of(2S)-2-(3-((1S)-5-(11-(4-(4-(bis(carboxymethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid (11.8 mg, 0.00915 mmol). The reaction mixture was heated at 90° C.for 1 hour and then lyophilized to to give(2S)-2-(3-((1S)-5-(11-(4-(4-(bis(carboxymethyl)amino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex (12.0 mg) as a white solid. MS (ESI), 731.2(M/2+H)⁺.

Example 13.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid

To a DCM (2.0 mL) solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester)(Macrocyclics) (42.4 mg, 0.050 mmol) and cyanuric chloride (9.2 mg,0.050 mmol) was added DIPEA (0.10 mL) and the solution stirred at roomtemperature for 2 hours. After stirring the solvent was removed using astream of nitrogen gas to give a residue. This residue was dissolved inDMSO (1.0 mL) and the solution was contacted with methanamine (0.10 mL,2.0 M in THF) and K₂CO₃ (50 mg). The resultant suspension was stirred atroom temperature for 4 hours. (S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) was added then added to the DMSO solution and thereaction mixture was stirred at room temperature for an additional 24hrs prior to lyophilization to afford the crude triazine intermediate.Deprotection using TFA (3.0 mL) and DCM (1.0 mL) at room temperature,overnight followed by removal of the solvent using a stream of nitrogengave crude product which was purified by Biotage SP4 using a C18cartridge to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (10.8 mg) as a white solid. MS (ESI), 594.2 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid, (7.7 mg, 0.00649 mmol) was added LuCl₃ (0.63 mL of a 0.0103mmol/mL, 0.00649 mmol). The reaction mixture was heated at 90° C. for 1hour and then lyophilized to to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(methylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex (7.9 mg) as a white solid. MS (ESI), 680.2(M/2+H)⁺.

Example 14.(2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics) (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL) and the solution was stirred at roomtemperature for 2 hours. After stirring the solvent was removed under astream of nitrogen to give a residue which was dissolved in DMSO (1.0mL) prior to the addition of (S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) and K₂CO₃ (50 mg). The resultant suspension wasstirred at room temperature for 2 hours and3-(piperazin-1-yl)propan-1-amine (47 mg) was then added following whichthe reaction mixture was stirred dor an additional 16 hours at roomtemperature. Lyophilization after 16 hours afforded the crude triazineintermediate which was deprotected at room temperature, overnight usingTFA (2.0 mL) and DCM (1.0 mL). The deprotected product was purified byBiotage SP4 using a C18 cartridge to give(2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid (25 mg) as a white solid. MS (ESI), 650.3 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid (10.7 mg, 0.00824 mmol) was added LuCl₃ (0.80 mL of a 0.0103mmol/mL, 0.00824 mmol). The reaction mixture was heated at 90° C. for 1hour and then lyophilized to give(2S)-2-(3-((1S)-5-(11-(4-(4-(4-(3-aminopropyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)-1-carboxypentyl)ureido)pentanedioicacid lutetium complex (10.2 mg) as a white solid. MS (ESI), 736.2(M/2+H)⁺.

Example 15.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(carboxymethyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(carboxymethyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid

To a DCM solution (2.0 mL) of p-NH2-Bn-DOTA-tetra(t-Bu-ester)(Macrocyclics), (42.4 mg, 0.050 mmol) and cyanuric chloride (9.2 mg,0.050 mmol) was added DIPEA (0.10 mL) the resultant solution was stirredat room temperature for 2 hours. After stirring, the solvent was removedusing a stream of nitrogen to give a residue which was dissolved in DMSO(1.0 mL) prior to the addition of (S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) and K₂CO₃ (50 mg). The suspension thus obtained wasstirred at room temperature for 2 hrs and tert-butyl2-(piperazin-1-yl)acetate (50 mg) was then added to the reaction mixtureand stirring was continued at room temperature for an additional 16hours. Lyophilization of the reaction mixture at the end of 16 hoursafforded a residue of the protected final product. This residue wascontacted with TFA (2.0 mL) and DCM (1.0 mL) at room temperatureovernight to cause removal of protecting groups, following which thesolvent was removed under a stream of nitrogen to give crude deprotectedproduct that was purified by Biotage SP4 using a C18 cartridge. Thetitled compound(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(carboxymethyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (14 mg) as obtained as a white solid. MS (ESI), 650.8 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(carboxymethyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(carboxymethyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (6.0 mg, 0.00426 mmol) was added LuCl₃ (0.45 mL of a 0.0103mmol/mL, 0.00462 mmol). The reaction mixture was heated at 90° C. for 1hour and lyophilized to to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(carboxymethyl)piperazin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex (5.6 mg) as a white solid. MS (ESI), 736.8(M/2+H)⁺.

Example 16.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

Step 1.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid

To a solution of p-NH2-Bn-DOTA-tetra(t-Bu-ester) (Macrocyclics), (42.4mg, 0.050 mmol) and cyanuric chloride (9.2 mg, 0.050 mmol) in DCM (2.0mL) was added DIPEA (0.10 mL). Following stirring at room temperaturefor 2 hrs, the solvent was removed using a stream of nitrogen to give aresidue which was dissolved in DMSO (1.0 mL) prior to the addition of(S)-di-tert-butyl2-(3-((S)-1-(tert-butoxy)-1-oxo-6-(11-(piperazin-1-yl)undecanamido)hexan-2-yl)ureido)pentanedioate(37 mg, 0.05 mmol) and K₂CO₃ (50 mg). The suspension formed was stirredat room temperature for 2 hrs and 4-(piperidin-4-yl)butanoic acid (160mg) was then added to the suspension. After continuous stirring at roomtemperature for 72 hrs, the reaction was stopped by lyophilizatio toafford the protected triazine compound. Deprotection at roomtemperature, overnight using TFA (4.0 mL) and DCM (1.0 mL), followed bypurification using Biotage SP4 and a C18 cartridge gave(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (15.3 mg) as a white solid. MS (ESI), 650.8 (M/2+H)⁺.

Step 2.(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex

To solid(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid (6.9 mg, 0.00520 mmol) was added LuCl₃ (0.50 mL, 0.0103 mmol/mL,0.00520 mmol). The reaction mixture was heated at 90° C. for 1 hour andlyophilized to to give(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(4-(3-carboxypropyl)piperidin-1-yl)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid lutetium complex (7.9 mg) as a white solid. MS (ESI), 750.2(M/2+H)⁺.

Example 17. ⁶⁸Ga Labeling of(2S)-2-(3-((1S)-1-carboxy-5-(11-(4-(4-(dimethylamino)-6-((4-((1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecan-2-yl)methyl)phenyl)amino)-1,3,5-triazin-2-yl)piperazin-1-yl)undecanamido)pentyl)ureido)pentanedioicacid

⁶⁸Ga was synthesized using a gallium-68 generator (IDB Holland). A 1 mLfraction of the generator eluate (eluted using 0.6 M HCl suprapure)containing the highest 68Ga activity was mixed with the reaction mixturethat containing 2 μL of the target compound (10 mM solution in DMSO) and10 μl of ascorbic acid (20% in water). The pH of the reaction mixturewas adjusted to be in the pH range of 3.6-3.9 by the addition ofapproximately 290 μL of an aqueous solution of sodium acetate (2.5 M inwater).

The mixture was heated at 90° C. for 10 minutes with stirring. A testsample of the reaction mixture was analyzed by HPLC to confirm completecomplexation. The reaction mixture was then diluted with 2 ml saline(0.9% sodium chloride) and loaded onto a pre-conditioned Plexa Cartridge(60 mg, Varian, Bond Elut Plexa). The cartridge was rinsed with 2 mLsaline prior to elution of the desired complex using 0.5 mL ethanol. Theeluent was passed through a sterile filter (Millipore, Millex-GV) fittedto a syringe followed by washing of the filter by passing 5 mL of salineand 200 μL of phosphate buffer.

The radio-labelled compound was analyzed by HPLC on a ChromolithPerformance RP-18e column (100×3 mm Merck KGaA, Darmstadt, Germany)using a linear gradient from 0% to 100% acetonitrile in water (bothcontaining 0.1% TFA) over 5 min. UV absorbance was detected at 214 nm.Under these conditions ⁶⁸Ga-MIP-1558 is eluted at about 2.25 min. Theradiochemical yields ranged from 77%-97%, average RCP=87% (datacorrected for radioactive decay).

EQUIVALENTS

While certain embodiments have been illustrated and described, it shouldbe understood that changes and modifications can be made therein inaccordance with ordinary skill in the art without departing from thetechnology in its broader aspects as defined in the following claims.

The present disclosure is not to be limited in terms of the particularembodiments described in this application. Many modifications andvariations can be made without departing from its spirit and scope, aswill be apparent to those skilled in the art. Functionally equivalentmethods and compositions within the scope of the disclosure, in additionto those enumerated herein, will be apparent to those skilled in the artfrom the foregoing descriptions. Such modifications and variations areintended to fall within the scope of the appended claims. The presentdisclosure is to be limited only by the terms of the appended claims,along with the full scope of equivalents to which such claims areentitled. It is to be understood that this disclosure is not limited toparticular methods, reagents, compounds compositions or biologicalsystems, which can of course vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember, including the first and last number listed for the range.

All publications, patent applications, issued patents, and otherdocuments referred to in this specification are herein incorporated byreference as if each individual publication, patent application, issuedpatent, or other document was specifically and individually indicated tobe incorporated by reference in its entirety. Definitions that arecontained in text incorporated by reference are excluded to the extentthat they contradict definitions in this disclosure.

Other embodiments are set forth in the following claims.

What is claimed is:
 1. A metal complex comprising actinium and acompound represented by Formula I

wherein: A is (CHR¹)_(m) or C(O); W is —C(O)—(CH₂)_(p)—;—C(O)[—CH₂—CH₂—O]_(n)—, —[CH₂—CH₂—O]_(n)—(CH₂)₂—,—C(O)—[CH(R³)_(t)]_(q)—, —(CH₂)_(m)—O—(CH₂)_(n)—,—(CH₂)_(m)—S—(CH₂)_(n)—, —(CH₂)_(m)—S(O)—(CH₂)_(n)—,—(CH₂)_(m)—S(O)₂—(CH₂)_(n)—, or —(CH₂)_(m)—NR_(a)—(CH₂)_(n)—, Y is —NH—,—NR²—, or

X is —(C₁-C₁₀)alkylene-(C₃-C₁₀)arylene, —(C₃-C₁₀)arylene,—(C₃-C₁₀)arylene-(C₁-C₁₀)alkylene-, phenylene,—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkylene, —(C₃-C₁₀)cycloalkylene, or—(C₃-C₁₀)cycloalkylene-(C₁-C₁₀)alkylene-; R¹ and R² are eachindependently H, —(C₁-C₁₀)alkyl, —C(O)—(C₁-C₁₀)alkyl, benzyl,—(C₃-C₁₀)cycloalkyl, or —(C₃-C₁₀)aryl; R^(a) and R^(b) are eachindependently H, —OH, —(C₁-C₁₀)alkyl, —[CH₂—CH₂—O]_(n)—(CH₂)₂-T,—C(O)—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—Z,benzyl, —(C₃-C₁₀)cycloalkyl, —(C₃-C₁₀)aryl-(C₁-C₁₀)alkylene,—(C₃-C₁₀)aryl, halo-(C₁-C₁₀)alkyl, hydroxy-(C₁-C₁₀)alkyl,—NH—(C₁-C₁₀)alkyl, or —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, or R^(a) and R^(b)together with the nitrogen to which they are bonded form a(C₃-C₆)-heteroaryl or (C₃-C₆)-heterocycloalkyl; Z is —OH,—O(C₁-C₁₀)alkyl,

R^(c) is —OH, —O(C₁-C₁₀)alkyl, -Obenzyl, —O(C₃-C₁₀)cycloalkyl,—O(C₃-C₁₀)aryl, —O—(C₁-C₁₀)alkylene-(C₃-C₁₀)aryl, or—O—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkyl, R³ is H, halogen, —OH, —NH₂,—(CH₂)_(p)—COOH, or —(CH₂)_(p)— NH₂; T is —H, —OH, —COOH, or—NR^(d)R^(e); R^(d) and R^(e) are each independently H, bond, —OH,—(C₁-C₁₀)alkyl, or —(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene; m, n, p, q, tand r are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10; and Dis

wherein any alkyl, alkylene, aryl, arylene, heteroaryl, heteroarylene,cycloalkyl, cycloalkylene, heterocycloalkyl, or heterocycloalkylene isoptionally substituted with 1, 2, or 3 substituent groups selected fromthe group consisting of —(C₁-C₁₀)alkyl, —(C₁-C₁₀)haloalkyl, —(C₁-C₁₀)aminoalkyl, —(C₁-C₁₀)alkylene-COOH, —(C₁-C₁₀)hydroxyalkyl, —OH, halogen,—NH₂, —COOH, —C(O)—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkylene-C(O)—,—(C₁-C₁₀)alkylene-C(O)—X, —NH—(C₁-C₁₀)alkyl, and—(C₁-C₁₀)alkylene-NR^(d)R^(e)—, and —NR^(d)R^(e).
 2. The metal complexof claim 1, wherein X is phenylene, r is 1 and D is


3. The metal complex of claim 2, wherein the compound is represented byFormula (II)

wherein: A is (CHR¹)_(m) or C(O); W is selected from the groupconsisting of —C(O)—(CH₂)_(p)—; —C(O)[—CH₂—CH₂—O]_(n)—,—[CH₂—CH₂—O]_(n)—(CH₂)₂—, —C(O)—[CH(R³)_(t)]_(q),—(CH₂)_(m)—O—(CH₂)_(n)—, —(CH₂)_(m)—S—(CH₂)_(n)—,—(CH₂)_(m)—S(O)—(CH₂)_(n), —(CH₂)_(m)—S(O)₂—(CH₂)_(n)—, and—(CH₂)_(m)—NR_(a)—(CH₂)_(n)—, Y is selected from —NH—, —NR²— or

R¹ and R² are each independently selected from H, —(C₁-C₁₀)alkyl,—C(O)—(C₁-C₁₀)alkyl, benzyl, —(C₃-C₁₀)cycloalkyl, or —(C₃-C₁₀)aryl;R^(a) and R^(b) are each independently selected from the groupconsisting of H, —OH, —(C₁-C₁₀)alkyl, —[CH₂—CH₂—O]_(n)—(CH₂)₂-T,—C(O)—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—Z,benzyl, —(C₃-C₁₀)cycloalkyl, —(C₃-C₁₀)aryl-(C₁-C₁₀)alkylene,—(C₃-C₁₀)aryl, halo-(C₁-C₁₀)alkyl, hydroxy-(C₁-C₁₀)alkyl,—NH—(C₁-C₁₀)alkyl, and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, or R^(a) andR^(b) together with the nitrogen to which they are bonded form a(C₃-C₆)-heteroaryl or (C₃-C₆)-heterocycloalkyl; Z is selected from —OH,—O(C₁-C₁₀)alkyl,

R^(c) is selected from —OH, —O(C₁-C₁₀)alkyl, -Obenzyl,—O(C₃-C₁₀)cycloalkyl, —O(C₃-C₁₀)aryl, —O—(C₁-C₁₀)alkylene-(C₃-C₁₀)aryl,or —O—(C₁-C₁₀)alkylene-(C₃-C₁₀)cycloalkyl, R³ is selected from H,halogen, —OH, —NH₂, —(CH₂)—COOH, or —(CH₂)—NH₂; T is selected from —H,—OH, —COOH, or —NR^(d)R^(e); R^(d) and R^(e) are each independentlyselected from H, bond, —OH, —(C₁-C₁₀)alkyl, or—(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene; m, n, p, q, t and x are eachindependently 0, 1, 2, 3, 4, 5, 6, 7, 8 9, or 10; wherein any alkyl,alkylene, aryl, arylene, heteroaryl, heteroarylene, cycloalkyl,cycloalkylene, heterocycloalkyl, or heterocycloalkylene is optionallysubstituted with 1, 2, or 3 substituent groups selected from the groupconsisting of —(C₁-C₁₀)alkyl, —(C₁-C₁₀)haloalkyl, —(C₁-C₁₀) aminoalkyl,—(C₁-C₁₀)alkylene-COOH, —(C₁-C₁₀)hydroxyalkyl, —NH₂, —COOH,—C(O)—(C₁-C₁₀)alkyl, —(C₁-C₁₀)alkylene-C(O)—, —(C₁-C₁₀)alkylene-C(O)—X,—NH—(C₁-C₁₀)alkyl, and —(C₁-C₁₀)alkylene-NR^(d)R^(e)—, and —NR^(d)R^(e).4. The metal complex of claim 3, wherein A is (CHR¹)_(m) and W is—C(O)—(CH₂)_(p)—.
 5. The metal complex of claim 4, wherein W is—C(O)—(CH₂)₇— or —C(O)—(CH₂)₁₀—.
 6. The metal complex of claim 4,wherein R¹ is hydrogen and m is
 2. 7. The metal complex of claim 3,wherein Y is —NH— or


8. The metal complex of claim 7, wherein Y is


9. The metal complex of claim 3, wherein R^(a) and R^(b) are eachindependently hydrogen or methyl and R^(c) is —OH.
 10. The metal complexof claim 3, wherein R^(a) and R^(b) together with the nitrogen to whichthey are bonded form a (C₃-C₆)-heterocycloalkyl.
 11. The metal complexof claim 10, wherein the (C₃-C₆)-heterocycloalkyl is selected frompiperidine, piperazine, morpholine, thiomorpholine, isothiazolidine,isoxazolidine, pyrrolidine, immidazolidine, thiazolidine or oxazolidine.12. The metal complex of claim 11, wherein the (C₃-C₆)-heterocycloalkylis piperidine or 4-(piperidin-4-yl)butanoic acid.
 13. The metal complexof claim 10, wherein R^(a) is —H and R^(b) is


14. The metal complex of claim 10, wherein R^(d) and R^(e) are eachindependently —(C₃-C₁₀)heteroaryl-(C₁-C₁₀)alkylene.
 15. The metalcomplex of claim 10, wherein R^(d) and R^(e) are each independently


16. The metal complex of claim 1, which is:

or a pharmaceutically acceptable salt or solvate thereof.
 17. The metalcomplex of claim 1, wherein the actinium is ²²⁵Ac.
 18. The metal complexof claim 16, wherein the actinium is ²²⁵Ac.
 19. A pharmaceuticalcomposition comprising the metal complex of claim 1, or apharmaceutically acceptable salt, solvate, or ester thereof; and apharmaceutically acceptable carrier.
 20. A pharmaceutical compositioncomprising the metal complex of claim 16, or a pharmaceuticallyacceptable salt, solvate, or ester thereof; and a pharmaceuticallyacceptable carrier.
 21. A method of obtaining a radiographic image ofone or more tissues that express prostate-specific membrane antigen(PSMA), the method comprising contacting one or more tissues thatexpress PSMA with the metal complex of claim 1, and obtaining aradiographic image of the one or more tissues.
 22. A method of obtaininga radiographic image of one or more tissues that expressprostate-specific membrane antigen (PSMA), the method comprisingcontacting one or more tissues that express PSMA with the metal complexof claim 16, and obtaining a radiographic image of the one or moretissues.